Infomédula Nº33 (inglés)

The Foundation for Research and Integration of the

National Hospital for Paraplegics (HNP) has as itsobjective the promotion, coordination and develop-ment of research programs applicable to Biomedi-cine and Health Sciences (especially those

programs pertinent to health promotion and disease preven-tion), improvement of health care, as well as social assistanceand rehabilitation of affected individuals. Furthermore, itseeks to facilitate research and research training in collabo-ration with the University, public and private institutions thatwork in this field.

The Research Management Unit (UGI) operatesfunds and resources dedicated to the development and exe-cution of research projects, technological development andinnovations. Since such aid often entails important manage-ment tasks, the UGI project managers act as important in-termediaries between researchers and funding entities,handling both national and international projects.

The UGI’s main activities are the following:� Advice, management and administrative sup-

port for research grants and clinical trials applications, rese-arch agreements, stipends and awards.

� Personalized advice for submitting grant ap-plications.

� Economic justification and modifications ofgrants’ budgetary items.

� Comprehensive management of research pro-jects and clinical trials including their logistics, economic/or-ganizational aspects and human resources.

� Resolution of personal enquiries.� Advice, support and management of intellectual

property underwriting original results.� Providing information on funding opportunities.� Organization of outreach events.� Organization of professional courses and/or con-

ferences.The UGI´s international projects management aims

to improve access to and success in achieving funding fromEuropean and international R & D programs. In this context aspecial attention is dedicated to the EU Research and Innova-tion Program Horizon 2020, a flagship initiative aimed at se-curing Europe's global competitiveness. This program bringstogether and strengthens the activities previously funded bythe 7th Framework Program for Research and Development(2007-2013), such as activities under the Competitiveness andInnovation Program (CIP) and activities of the European Ins-titute of Innovation and Technology (EIT).

The UGI also aims to increase the presence and par-ticipation of the HNP researchers in European and internatio-nal R & D programs, especially in Horizon2020 calls, and toeffectively manage the international and European funds. Theservice performs the following activities:

� Offers advice with proposal designing, draftingand processing.

� Help with the budget development.� Proposal presentation using the European Com-

mission online platforms-i.e. participant’s portals.� Administrative support during the negotiation

process with the EU commission and during the process ofsigning of consortium agreements and funding.

� Assistance during the project execution.� Request for budgetary changes and budget com-

pliance.� Project expenses justification.� Dissemination of project results and updates of

the project’s web site.� Organization of Consortium meetings and disse-

mination events.� Providing information on upcoming project calls,

information sessions and networking events.� Assistance in finding project partners.The Foundation´s Research Management Unit pre-

sently counts with the staff of six. Three of them manage theFoundation´s administrative and fi-nancial issues while the reaming threeperform tasks related to the nationaland international research projects.

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Photo: Carlos Monroy(Left to right) Silvia Díaz, Beatriz Gallego, Susana Fernández and Julio López.

Judging by the number and likely causes, the spinalcord injury presents a global problem. It is estima-ted that there are millions of spinal cord injured pe-ople worldwide with the yearly incidence varying

from 40-55 persons, per million of habitants, in the USand Japan, 30 in Australia to 20-30 people in Europe. Ho-wever, if we broaden the scope to include different centralnervous system (CNS) diseases, also addressed in some ofour basic research projects, these figures increase signifi-cantly. According to the World Health Organization(WHO) hundreds of millions of people around the worldsuffer from some form of neurological disorder, for exam-ple: 50 million people suffer from epilepsy, 62 millionfrom cerebrovascular diseases, 326 million from migraine,whereas 24 million people have the Alzheimer's diseaseor some other type of dementia.

The common cause of SCI have changed over theyears, mostly depending on the reality of each country andaccompanying life style change. Recent clinical statisticsat the National Hospital for Paraplegics indicate a generaldecline in the number of traumatic injuries caused by traf-fic accidents and an increase in the number of injuries cau-sed by falls, as well as an increase in hospitalizations dueto different spinal cord diseases.

Regardless of the cause that may produce it (i.e.trauma, infection, degenerative disorders, tumors, etc.),the enormous impact spinal cord injury exerts upon a pa-tient, his immediate surroundings and the whole societymakes it an area of great scientific interest.

Only half a century ago the life expectancy of aperson with paraplegia would hardly reach a couple ofyears. Thanks to scientific and technological advances, cu-rrent survival rate and life quality of these persons haveundergone numerous positive changes. The knowledgeand experience accumulated by professionals at the HNP,during almost forty years of its history, has contributedsignificantly to this trend.

Despite numerous advances in this field, clini-cians at the center are faced daily with the same questionposed by patients and their families: Is there a cure for spi-

nal cord injury? In the last five years, new tools and tech-

niques for restoring damaged nervous systembecame available but most of them have onlybeen approved for animal, especially rodent,

use. Although, these new techniques are being graduallyapplied to some human spinal cord injuries, there is still along way to go.

Fortunately, a growing body of data, more politi-cal willpower and the available financial and human re-sources are bringing us closer to crossing the final sciencefrontier: the nervous system.

Two following examples speak in favor of thisnotion: under the platform "Horizon 2020" , the EuropeanCommission has decided to invest billions of euros in the"Human Brain" project, as well as in the project with gra-phene, a conductive material used as three-dimensionalscaffold upon which long neuronal processes, calledaxons, can grow. The Commission indicates that the aboveprojects will be the most advanced studies ever conductedin this field and will serve to develop personalized treat-ments for various neurological disorders. At least 15 EUmember states, including Spain, are involved in these twostudies.

The other example can be found on the other sideof the Atlantic where, a Spanish scientist, Rafael Yuste co-ordinates the United States-led initiative of Obama Admi-nistration, known as BRAIN (Brain Research throughAdvancing Innovative Neurotechnologies) and aimed atmapping out all brain activities in the next 15 years. Theidea, originally conceived by the Spanish scientist, cu-rrently involves hundreds of experts from around theworld and provides yet another example of globalization.

Neurobiologists seem to agree that therapies aimedat the spinal cord regeneration have to incorporate severalstrategies at once. In line with that, scientists at the HNP areworking on the most promising strategies that would allowpatients to maximize their functional recovery.

Taking into account basic and clinical researchadvances in the field of spinal cord injury, one may askthe following questions: How do we translate these advan-ces in terms of patients’ hope? To which extent the availa-ble information is shared and coordinated betweenresearchers working on neural regeneration worldwide?

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E xperimental Neurology Unit of theHNP was founded in 2002 with onlytwo laboratories and the objective ofdeveloping basic research in the field

of spinal cord injury. Currently the unit inclu-des more than a hundred researchers dividedbetween eighteen research groups (basic andclinical) and the research support units (i.e.microscopy, flow cytometry, proteomics, MRIand animal facility). They work together tobetter understand the biology of spinal cord in-jury.

The Research Foundation of the HNPwas created in 2004 to provide administrativesupport to researchers, to capture and managefinancial resources, to inform the healthcareprofessionals and society about the latest ad-vances in neuroscience research while ensu-ring legal and ethical principles in the researchprocess. Furthermore, much of the Founda-tion´s effort is dedicated to the developmentof a financially sustainable system by attrac-ting the national and international funds, spon-sorships and volunteer work. This way weexpect to realize the work of quality and rele-vance to people with spinal cord injury andalso to the society as a whole.

Multidisciplinary research for the repair of spinal cord injuries

Research at the National Hospital for Paraplegics

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T he fundamental goal of research in the fieldof healthcare is to produce knowledge on themolecular, biochemical, cellular, genetical,pathophysiological and epidemiological me-

chanisms underlying diseases and health problems,in our case the spinal cord injury and CNS diseases,and to develop strategies for their prevention and tre-

atment. In the HNP are conducted two typesof research: basic/preclinical and clinical.Basic research seeks a better understandingof the molecular, biochemical and cellular

mechanisms involved in the origin and outcomes ofthe disease, as well as to determine the involvementof epigenetic aspects in its genesis.

Clinical research, on the other hand, is cen-tered on patients while realizing studies on the pre-vention, diagnosis and treatment of spinal cordinjury. Clinical trials play an important role in thistype of research as they serve to determine or verifyclinical and/or pharmacological effects of a particu-lar therapy, or an experimental compound, in orderto address their safety and effectiveness.

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NEURAL PLASTICITY-CAJAL INSTITUTE (CSIC, Dr. Manuel Nieto Sampedro)

NEUROINFLAMMATION(Dr. Eduardo Molina Holgado, Dr. Daniel GarcíaOvejero and Dr. Ángel Arévalo Martín)

NEURAL REPAIR AND BIOMATERIALS (Dr. Jorge Collazos Castro)

SENSORY-MOTOR FUNCTION (Dr. Julian Scott Taylor)

NEURONAL BIOENGINEERING (Dr. Guglielmo Foffani )

EXPERIMENTAL NEUROPHYSIOLOGY (Dr. Juan de los Reyes Aguilar Lepe)

MOLECULAR NEUROPROTECTION (Dr. Rodrigo Maza y Dr. Manuel Nieto Díaz)

MOLECULAR NEUROLOGY (Dr. Francisco Javier Rodríguez Muñoz)

DEVELOPMENTAL NEUROBIOLOGY(Dr. Fernando de Castro)

MEMBRANE BIOLOGY AND REPAIR AXONAL (Dr. José Abad Rodriguez)

VASCULAR PATHOPHYSIOLOGY (Dr. María G. Barderas y Dr. Luis R. Padial )

NERVE REGENERATION AND NEUROCHEMISTRY(Dr. Jörg Mey and Dr. Ernesto Doncel Pérez)

FUNCTIONAL EXPLORATION ANDNEUROMODULATION OF THE CENTRAL NERVOUS SYSTEM (GRUPO FENNSI, Dr. Antonio Oliviero)

BIOMECHANICS AND TECHNICAL AID(Dr. Angel Gil)

GAIT RE-EDUCATION AND FUNCTIONAL RECOVERY (Dr. Ana Esclarín de Ruz)

ASSISTED REPRODUCTION (Dr. Eduardo Vargas)

SPINE PATHOLOGY(Dr. Andrés Barriga Martín)

UROLOGY(Dr. Manuel Esteban)

Research Research

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The following dossier was prepared by the National Hospital for Paraplegics´ Commuication Office(Miguel Á. Pérez Lucas, Elena López and Carlos Monroy), with translation and assessment by

Dr. Ksenija Jovanovic and the invaluable contribution of the principal investigators and heads of the research support units.

Reducing the death of neurons and oli-godendrocytes or replacing them

The death of a large number of these cellsduring the acute phase and during, so called, secon-dary cell death is responsible for much of the func-tional loss. Following their death, our body is notcapable of replacing them as both cell types are notproduced during adulthood and the amount that isgenerated from stem cells or precursors is verylimited.

Promoting axonal regenerationIn other words, to make axons severed

by the injury grow again and cross the injuredarea in order to restore interrupted spinal cir-cuits. In principle, spinal axons have the abilityto grow but do so very slowly and once theyreach the injured area they encounter an inhibi-tory environment that impedes their growth. Theculprits for this situation are myelin proteins suchas MAG (myelin associated glycoprotein), Nogo,MOGP (myelin associated oligodendrocytic glyco-

protein) or Tenascin, released in the injured area fo-llowing oligodendrocyte cell death. Other molecules

from the glycosaminoglycan family, present in glialscar-forming reactive astrocytes, also cause the inhibition.

Promoting axon remyelinationThe loss of myelin, resulting from the death of oligo-

dendrocytes, leads to a poor nerve signals conduction in sur-viving axons. Therefore, remyelination of axons raises thepossibility of improving their function even in the absence of axo-nal regeneration.

Reconnecting damaged circuitsThis approach involves processes that allow axons to

reconnect with their targets. Certain molecules, important in axo-nal guidance during our development and growth, are alsothought to be important in this process. Badly reconnected circuitsmay function even worse than the injured ones, thus producingundesirable consequences as neuropathic pain, spasticity and ge-neral circuit malfunctioning This is the least explored area in thespinal cord repair, mainly because it requires that the above men-tioned problems are solved first.

by Manuel Nieto Diaz, Research scientist at the HNP

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To repair a spinal injury means to restore, albeit partially, functions damaged by the injury by restoring,to some extent, the structure and circuitry that existed prior to it.

This entails solving several problems:

The complexity and large number of processes triggered by the spinal cord injury have led to an equi-valent number of research lines addressing its repair in very different, but largely complementary, ways. Someof these therapeutic approaches focus on only one aspect of the injury, while a great number of them attemptsto solve several problems at once.

Basic approaches can be classified into:

Transplantation: involves insertion of some tissue or material in the injured area to help repair the damage. The most commontransplantation candidates include fetal spinal cord tissue, peripheral nerve grafts, different types of cells (neural or not) and even biomaterials.

Molecular strategies: assume introduction of specific molecules that promote axonal regeneration directly or by inactivating mo-lecules that inhibit axonal growth. This type of strategy also includes molecular neuroprotection with substances that promote the survival ofneurons and oligodendrocytes.

Promotion of alternative circuits: the nervous system has the capacity to change and adapt and is able to employ alternativecircuits to perform some of the functions lost after spinal cord injury.

Other types of strategies may be based, for example, on biophysical factors as electrical activity that is capable of promoting the growth of axons and guiding them towards proper targets.

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La calidad de vida de las personas es nuestra prioridad

Coloplast Productos Médicos, S. A. Condesa de Venadito 5, 4ª planta - 28027 Madrid. España

Tel 91 314 18 02 - Fax 91 314 14 65 - Email: [email protected]

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Todos los derechos reservados por Coloplast Productos Médicos, S.A.

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Neural Plasticity-Cajal Institute

Main investigator

www.neuralrepairhnp.com

Lesions in the central nervous system (CNS) of adult mam-mals, being mechanical or degenerative, are not spontaneously repai-red. One of the main obstacles is the formation of a fibrogliotic scar atthe injury site. Although important in organism survival, the scar hin-ders growth of regenerating fibers towards their physiological targetsand causes atrophy (i.e. collapse) of their growth cones.

For the last 35 years, the principal investigator has beenstudying the molecular bases of neural plasticity and their possibleuse in functional repair of the CNS injuries.

The present work topics of the group are:Cell culture models of reactive glia.Cellular and molecular mechanisms involved in glial scar

formation.Inhibition of glial scar formation by natural and synthetic

compounds.

Manuel Nieto-Sampedro has devoted 46 years of his pro-fessional life to clinically oriented basic research. The first eight yearsof his career were dedicated to the action mode of antibiotics, while inthe remaining years he studied neural plasticity.

His main accomplishments are the following:First description of the mode of action

of antibiotics that inhibit the synthesis of bacterialcell wall proteoglycans (penicillins, cephalospo-rins, vancomycin, ristocetin).

Structure and conformation of energytransducing ATPase.

First description of the synapse specificantigen PSD-95.

First description of injury-induced CNSneurotrophic activity and of glia as its main cellularsource.

First descriptionof the correlation of in-jury-induced neurotrophicactivity and enhancedsurvival and integrationof delayed transplants inthe CNS wound cavity.

First description of the relationship between the nervousand immune system (first description of the presence of cytokines IL-1 and IL-2 in the brain).

First description of the regeneration, spinal cord re-entryand functional recovery of axons after dorsal rhizotomy.

First description and chemical purification of normal andinjured CNS proteoglycans that negatively regulate axonal growth.

First description, chemical purification and structure deter-mination of a glycolipid (neurostatin) that negatively regulates proli-feration of cells of astroglial lineage.

Production of synthetic and semi-synthetic analogues of theglial division inhibitor, neurostatin.

Production of synthetic and semi-synthetic inhibitors ofbrain and spinal cord tumors (glioblastoma).

First studies on cytokine IL-15, as the initiator of glial re-activity and neuropathic pain following spinal cord lesions.

During the past decades the principal investigator has main-tained numerous and friendly scientific collaborations, some of whichare still active while others could be activated if required.

Some of his distinguished collaborators are: Dr. Håkan Ald-kogius (Biomedical Center, University of Uppsala, Sweden). Dr. JohnP. Fraher (Department of Anatomy, University of Cork, Irland). Dr.Stephen B. Mc Mahon (St Thomas Hospital, London, UK). Dr. JohnV. Priestley (Division of Physiology, St Mary's Hospital, London, UK).

The problem

The Research

Collaborations

Progress

Photo: Carlos Monroy(Left to right) Manuel Nieto Sampedro, Natalia Yanguas Casás, Asunción

de la Barreda Manso, Estela Dámaso Riquelme and Lorenzo Romero Ramírez.

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The group video

Neuroinflammation


Spinal cord injury presents a complex reality and to improveit and/or counteract it we must address numerous pathological processes.Our laboratory is focused on the study and therapeutic modulation offour events that occur after the injury: 1- the death of nerve cells (neu-rons and glia), resulting in the loss of neural function; 2- the inflamma-tory response, which in acute phase (days following the injury)contributes to the spread of spinal damage, while in chronic phase(months and years later) is one of the possible causes that prevent neuralregeneration; 3- axonal dysfunction due to the loss of the myelin sheet;4- the response of neural stem cells or spinal precursors to spinal cordinjury.

Our laboratory has more than 15 years of experience in stud-ying the endocannabinoid system. Endocannabinoids are substances ourbody naturally makes out of cell membrane lipids and are named afterthe active ingredients of marijuana, which in turn exert their effects byacting through the receptors of this system. Our results so far demons-trate that endocannabinoids may serve as a therapeutic target for signi-ficantly reducing the first three of the above mentioned problems.

We are also studying spinal cells (called neural precursors orstem cells) that could give rise to new cells following injury in the spinalcord of rats and mice, as well as in humans. Furthermore, we are explo-ring whether autoimmunity (i.e. immune system attack against its ownnervous tissue) slows spontaneous recovery after a spinal injury.

We have shown that the endocannabinoid system is activatedfollowing a spinal cord injury and that exogenous administration of theprincipal endocannabinoid, 2-arachidonylglycerol, reduces the injury-in-duced tissue damage. In contrast, blocking the "natural", endogenous ac-tivation of this system, changes the spinal cord inflammatory profile,increases the neurological damage and causes more functional loss. Thespinal injury research has advanced tremendously in determining whichpathogenic mechanisms must be contained to prevent the damage fromspreading. However, what we have found is the opposite: an endogenousdefense mechanism that must be potentiated to counteract the injury.

Furthermore, we have observed that the endocannabinoidsystem promotes proliferation and preservation of neural stem cells inthe rat and mouse. However, our findings demonstrate that the regionhousing these cells is very different between humans and experimentalanimals, which could have important implications when it comes to trans-ferring these results to the clinic. We are presently trying to understandthe mechanisms underlying this difference and to "humanize" this regionto have an experimental rat model that faithfully mimics what happensin humans and thus, explore how we could exploit this region to repairhuman spinal cord.

Finally, we have shown that the endocannabinoid system pro-motes the migration and maturation of oligodendrocyte precursors, cellswhich produce the myelin sheath, and that treatment with substances thatactivate cannabinoid receptors leads to an increase in myelination duringdevelopment in rats and mice, as well as in mice with multiple sclerosis.We are currently evaluating whether this therapeutic potential is appli-cable to spinal cord injury.

Dr. Carmen Guaza (Instituto Cajal, CSIC, Madrid). Dr. LukasGrassner (Center for Spinal Cord Injuries, Trauma Center Murnau, Ger-many and Institute of Molecular Regenerative Medicine, SCI-TReCS,Paracelsus Medical University, Salzburg, Austria). Dr. Francisco Molina-Holgado (Neural Stem Cell Laboratory, University of Roehampton, Whi-telands College, United Kingdom). Dr. José Florensa Vila (Departmentof Radiology, National Hospital for Paraplegics, SESCAM, Toledo). Dr.Isidro Ferrer (Institut de Neuropatologia, Servei d’Anatomia Patolo‘gica,IDIBELL-Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat).Dra. Florencia Labombarda, (Laboratory for Neuroen-docrine Biochemistry, Institute of Biology and Expe-rimental Medicine, CONICET y Department ofHuman Biochemistry, Faculty of Medicine, Universityof Buenos Aires, Argentina).

The problem

Collaborations

The Research

Progress

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The group video

Main investigators

Photo: Carlos Monroy(Left to right) Jorge Díaz-Rullo, Uyen Le, Ángel Arévalo, Daniel García, Concepción Sánchez-Caro and Eduardo Molina.

Neural Repair and Biomaterials

Main investigator


Following human spinal cord injuries neural tissue isdestroyed for several centimeters, thus forming cavities and scarsthat prevent axonal regeneration and directed cell migration. Torepair these injuries and achieve functional recovery, it is neces-sary to design three-dimensional substrates made of biomaterialsthat provide support to neural cells and that stimulate and guideaxonal growth. Furthermore, to be able to investigate how func-tional alterations occur and to evaluate potential treatments, it isnecessary to activate the intrinsic regenerative ability of neuronsand develop animal models relevant to the human pathology.

With the goal of promoting reparative processes follo-wing spinal cord injury, our laboratory opts for a comprehensiveapproach based on three pillars:

- Development of implantable devices using electro-con-ductive microfibers functionalized to provide support, guidanceand stimuli to axonal growth and cell migration.

- Pharmacological and genetical activation of intrinsicmechanisms that induce neuronal axonal regeneration.

- Dynamic control of cellular responses by means ofelectrostimulation.

At the same time, we investigate the loss of function,compensation and functional recovery after spinal injury, by usinga combination of high resolution kinetics and kinematics for themotility evaluation, as well as models of the most frequent humaninjuries. Besides the biomechanical analysis of residual motor ca-pacity, we employ anterograde and retrograde tracers to determinealterations in the underlying neural circuitry.

We have developed bioelectrochemical methods for con-trolling neural growth on conducting polymers, as well as mole-

cular complexes to functionalize theelectroconducting surfaces to selecti-vely stimulate axonal growth and/orproliferation and migration of glial pro-genitors. Likewise, we manufacture

electroconductive microfibers that promote axonal growth and cellmigration over long distances (i.e. 8 mm in 10 days), and that pro-mote and guide axonal growth after spinal cord injury in animalmodels.

On the other hand, we have described the pathophysio-logy of locomotor disorders and damaged neural circuits after cer-vical, thoracic and lumbar spinal injuries, thus obtaining a reliablecorrelation between anatomical structure and function that allowsus to properly evaluate outcomes of various therapeutic interven-tions. Finally, we have determined how to compensate for lostmotor functions, information that results critical for optimizingfunctional rehabilitation protocols.

To advance in such a complex research topic, teamworkis essential. Therefore, we have established collaborations with re-search groups in Spain (the CSIC and University of Castilla LaMancha), as well as with research institutions in the United King-dom, Greece and Portugal. Our current efforts are directed at de-veloping collaborations with the pharmaceutical andmicro/nanotechnology industry. In particular, we are beginning tointeract with French companies specialized in these fields in orderto manufacture implantable electrobiológical devices for humanspinal cord repair.

The problem

Photo: Carlos Monroy(Left to right) Concepción García-Rama, Francisco Ankor González,

María Concepción Serrano, Hugo Vara, Jorge Collazos, Alejandra Alves and Isaac Alberca.

The Research Collaborations

Progress

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The group video

Sensori-motor Function

Main investigator


Spinal cord injury produces different degrees of sensation andmovement loss. However, the development of pain and spasticity, as themajor chronic complications, are often perceived as more debilitatingand contribute significantly to loss of quality of life. Failure to diagnoseand adequately treat these additional symptoms during the recovery pe-riod requires the development of new tests and treatment strategies. La-test evidence points to the possibility that these symptoms are related tothe type of injury, including bleeding within the injury area. These physi-cal factors and clinical symptoms negatively impact on the small amountof functional recovery driven by neurorehabilitation programs, and mayeven block new ways to treat spinal cord injury.

The research group, organized between the basic and clinicallabs, works to improve the diagnosis of spasticity and neuropathic painby measuring the changes in sensation and movement that occur afterspinal cord injury. In parallel, we work on developing new ways to treator prevent these debilitating complications so that the subject can recoveras much as possible.

To achieve these objectives we combine various experimentaltechniques to measure “pain” and “spasticity” in animal models and use

standard neurological and new diagnostic tests that can spot the most da-maging signs of these symptoms. In the basic lab, we employ a new scre-ening platform that helps us identify new treatments that could helpcontrol different types of spasticity and neuropathic pain. In the clinicallab, we perform investigator and industry lead clinical trials to improvethe diagnosis of these symptoms in the course of their rehabilitation inthe hospital and at home. This allows us to test standard and new treat-ment strategies in collaboration with our specialized medical staff.

Our group has developed two new drugs based on natural fattyacids that control several damaging symptoms of spasticity and pain. Im-portantly, these drugs also allow better movement recovery after injuryby making some surviving nerves grow more. A patented drug has alre-ady been registered as an orphan drug in Europe, while the others arebeing developed by industrial partners thanks to the new screening plat-form in our basic research lab.

At the clinical level, we are working on ways to give both thepatient and clinician, early warnings about the development of the mostdebilitating symptoms of pain and spasticity. The clinical trials in pro-gress, that include testing pharmacological, neuromodulation and trainingtechniques, will help to control some of these complications.

Our group collaborates with respected national andinternational experts at both the basic and clinical level in-cluding Dr. Martin Marsala (San Diego, USA), Dr. NannaFinnerup, (Arrhus, Denmark), Dr. Jose Luis Pons (Madrid,Spain), Dr. Volker Dietz (Balgrist, Switzerland), Dr. Mi-guel Ruiz (Madrid, Spain), Dr. Vivian Mushahwar (Ed-monton, Canada) and the Guttmann Institute (Badalona,Spain). Other strategic links include University of Liver-pool, University of Glasgow, as well as Stoke Mandevilleand the London Hospital. We work with industrial partnersinterested in related viable clinical solutions, especially Li-popharma S.L. (Palma de Mallorca, Spain). Our group isthe responsible Toledo arm of the European Medical Spi-nal Cord Injury and EuroDolmed net-work. Finally, we believe that goodsolutions emerge when we collaboratewith clinicians dedicated to the same pro-blems produced by spinal cord injury.

The problem

Collaborations

The Research

Progress

Photo: Carlos Monroy(Left to right) Juan Avendaño, Cristina Simón, Elisabeth Bravo, Julio Gómez, Águeda Ferrer, Iriana Galán, Gerardo Ávila and Julian S. Taylor.

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The group video

Neuronal Bioengineering

Main investigator


Neuronal activity represents the basis for informa-tion transmission in the nervous system. When the nervoussystem is damaged, for example due to a spinal cord injuryor a neurodegenerative disease, neuronal activity becomesaltered, leading to pathological consequences such as neu-ropathic pain in spinal cord injury or tremor in Parkinson’sdisease. In our group we address neurological problems fromthe perspective of the alteration in neuronal activity.

Modern neurophysiological techniques allowscientists to record neuronal activities of increasing comple-xity (e.g. populations of single neurons, local field poten-tials, multichannel EEG recordings, functional imaging, etc)but their very complexity often impedes the correct pa-thophysiological interpretation of the recorded activity. The-refore, the overall research theme of our group includes thedevelopment and application of methodologies for recordingand analyzing neural signals to extract pathophysiologicalinformation from complex neuronal activities. Specifically,our main research lines are the following: brain reorganiza-tion after spinal cord injury; neuronal oscillations in neuro-degenerative disorders; neural coding in the somatosensorysystem; development and application of neuromodulationtechniques to treat neurological disorders.

We have developed methods to exactlyquantify the information that neuronal po-pulations can transmit by means of thequantity or the temporal precision of theiractivity in physiological and pathological

conditions. One of the most fascinating consequences of thetemporal precision of neuronal activity is that large networksof interacting neurons tend to oscillate. Thus, we have ge-nerated a solid knowledge base about the role of cerebral os-cillations in spinal cord injury and in neurodegenerativediseases such as Parkinson’s disease and epilepsy. Regardingthe spinal cord injury problem, our results have immediatepractical consequences on the control of anesthesia in pa-tients, as well as far-reaching implications in the mecha-nisms that lead to brain reorganization after spinal cordinjury and a consequent emergence of neuropathic pain. Inline with that, we are presently developing novel techniquesfor brain stimulation to prevent/treat neuropathic pain afterspinal cord injury. So far, these techniques show very pro-mising potential in treating neurological disorders with highsocial impact, such as epilepsy and migraine. To maximizethe social impact of our research, we have created a spin-offcompany at the Fundación del Hospital Nacional de Para-pléjicos: Neurek S.L. (www.neurek.com).

The closest collaborators of the group are Dr. Juande los Reyes Aguilar and Dr. Antonio Oliviero at our insti-tution (also co-funders of Neurek S.L.), Dr. Liset Menéndezde la Prida at the Cajal Intitute in Madrid, Dr. Alberto Prioriat the University of Milan in Italy and Dr. Karen A. Moxonat Drexel University in the USA. Furthermore, every timewe send a paper to a scientific journal for possible publis-hing, that paper is sent to, at least two, other scientists whoact (for free) as anonymous reviewers, offering their opi-nions, suggestions and critique to improve the work or to re-ject it. We do the same with articles from other scientists.This means that any scientist who publishes and actively par-ticipates in the process of peer reviewing is continuously co-llaborating, in a very active way, with the internationalscientific community.

The problem

The Research

Progress

Collaborations

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The group video

Experimental Neurophysiology

Main investigator


The somatosensory system receives pe-ripheral signals in order to process all the infor-mation related to touch, proprioception, pain andtemperature. The system is composed of diffe-rent pathways that carry these signals throughstructures located at the level of the spinal cord,brainstem, thalamus and cortex. A spinal cordlesion interrupts the sensory pathways, whichcarry peripheral signals from the body regionsbelow the lesion level to the cerebral structuresof the somatosensory system. Furthermore, itcreates an imbalance in these structures becauseeach of them receives inputs from the intactbody areas but fails to receive inputs from theareas below the lesion.

It is well known that after a spinal cordinjury the somatosensory cerebral cortex under-goes reorganization; a phenomenon in which thedeafferented cortical area starts to respond to sti-mulation of intact body areas (i.e. above the le-sion level). This phenomenon develops in abroad time window (i.e. from months to years)and could be the origin of pathologies such asneuropathic pain and phantom limb. Therefore,it is very important to understand neurologicaleffects that a spinal cord injury triggers in cere-bral structures that fail to receive signals fromthe periphery, because an aberrant activity maybe the origin of various pathologies.

In our lab we use electrophysiologicalrecordings from cerebral cortex and thalamus in

animals under control conditions and after a spi-nal cord injury. More specifically we record theneural activity from thalamic and cortical re-gions corresponding to the forepaw and hind-paw, which allow us to compare neuronalactivity between the intact and deafferented re-gions at cortical and thalamic levels after a spi-nal cord injury. Consequently, these data arehelping us attain better understanding of thechange that happens in the brain after a spinalcord injury.

Our results show that spinal cord injury produ-ces an immediate change in the functional stateof the somatosensory cortex (switching it fromdelta activity to slow-wave activity). At thesame time, this change of spontaneous activitymodulates evoked responses in the intact cortex(the region that receives signals from above thelesion level). Moreover, our results demons-trate that both the intact and deafferented cor-tex undergo two processes related to immediatefunctional changes: the first one is state-depen-dent, as triggered by the state change, while thesecond one leads to state-independent increasedresponses in both cortical regions. Taken toge-ther, our results provide a close up view of thevery first moments follo-wing a spinal cord injury,thus allowing us to betterunderstand the initiation ofcortical reorganization, aprocess which ultimatelymay trigger different pa-thologies.

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The group video

Molecular Neuroprotection

Main investigators


Loss of sensation, motor skills and many otherfunctions that follow spinal cord trauma are not only dueto damage inflicted by the trauma, but also due to a cas-cade of subsequently released harmful signals that causea wave of cell death. Most of these cells die through dif-ferent forms of programmed "cell suicide" that occursroutinely in the human body but that greatly extends theinitial spinal cord damage, thus contributing to the lossof function.

Our group investigates the involvement of celldeath in spinal cord injuries (SCIs) and seeks therapiesthat protect cells after injury. There are several processesleading to programmed cell death, including apoptosis,necroptosis and autophagic death. While the involvementof apoptosis in spinal cord injury is well known, the con-tribution of the other two processes, and their potentialas therapeutic targets, remains virtually unknown. Thus, our work is cen-tered on assessing the implication of all these processes in spinal cord in-jury and on identifying ways to control them in order to reduce theireffects.

This last aspect has led us to study changes that different celldeath regulators undergo after SCI. More specifically, we are investigatinghow SCI alters the concentration, distribution and function of apoptosisregulatory proteins such as XIAP, microRNAs (small nucleic acid strandscapable of controlling cellular function), components of the purinergicsystem (systems of chemical communication between nerve cells) or dif-ferent bioactive lipids as sphingosine-1-phosphate (S1P). Our group hasalso developed studies in the field of nerve regeneration based on theanalysis of nerve growth processes that occur during spontaneous regene-ration of deer antlers, in order to identify mechanisms that can be appliedto neural repair. Knowledge about these cellular processes and their regu-lation is allowing us to evaluate new therapeutic strategies for spinal cordinjury.

Our researcah so far has produced severalimportant results. Our studies on the protectiveprotein XIAP have allowed us to confirm itsimportance in spinal injury and to test a treat-ment that enhances its activity, producing po-

sitive effects in animal models. Moreover, studies on microRNAs revealedthat spinal cord injury causes a general decline in the expression of theseregulators, thus facilitating the injury-triggered processes as cell death, in-flammation and/or nerve regeneration. On the other hand, the purinergicsystem studies indicate that the members of this family (called diadeno-sin-polyphosphates) help cell survival when administered to injured ani-mals, which translates into significant improvements in motor activity.

Promising results were also obtained from the study on bioac-tive sphingolipids, showing that a reduction in the S1P degrading enzymecauses greater conservation of neural tissue and improves motor outcomesafter spinal cord injury. These results, together with our ongoing work,point out to new targets and provide us with new therapeutic tools for thetreatment of spinal cord injury.

Our work is based on collaborations with other national and in-ternational researchers like Drs. Casas and Fabrias at the Institute of Ad-vanced Chemistry of Catalonia (CSIC, Barcelona, Spain), Prof. Dr. PaulP. Van Veldhoven at the Department of Cellular and Molecular Biology,´´LIPIT´´ (Leuven, Belgium), Prof. Dr. Dan Lindholm at Minerva Institutefor Medical Research ́ ´Biomedicum´´ (Helsinki, Finland), Prof. FranciscoJ. Esteban at the University of Jaen (Jaen, Spain), Dr. Jesus Pintor at theComplutense University (Madrid, Spain) and Dr. Chunyi Li at the Uni-versity of Otago (New Zealand) .

Photo: Carlos Monroy(Left to right) Rodrigo Martínez Maza, Marcos Caballero López,

Teresa Muñoz de Galdeano, David Reigada Prado, Rosa Navarro Ruiz, Manuel Nieto Díaz and Ángela del Águila Sánchez.

The problem

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The group video

Molecular Neurology

Main investigator


Spinal Cord Injury (SCI) is a major cause of functionaldisability yet without a standard, clinically accepted treatment.Functional impairments following SCI are produced by multi-fac-torial processes as a result of primary mechanical damage, secon-dary cell death and a low capacity of the CNS to regeneratedamaged axons and replace lost cells.

The Molecular Neurology Group was created in 2005with the objective of screening for new therapeutic targets and de-veloping combined therapies for neuroprotection and promotionof axonal regeneration and cell replacement. This broad experi-mental approach allows us to address the challenge of neural repairthrough multidisciplinary research ranging from its very molecularaspects to the correlation in motor and sensory functional outco-mes, electrophysiology and histology in clinically relevant rodentmodels of CNS and PNS damage.

Major research findings include the description of awide expression of the Wnt family of proteins in the adult spinalcord, with a key role after an injury, as well as the presence of anovel source or autologous stem cells located in the leptomeningesof the adult spinal cord, with the potential to generate new neuronsand oligodendrocytes. Our current research interests aim to unravelthe role of Wnts and Leptomeningeal Stem Cells (LeSCs) in thepathophysiology of spinal cord injury, to develop novel, drug-based therapies (e.g. leptin- and ibuprofen-based) and adult, auto-logous cell transplants (such as adipose mesenchymal cells)currently used in clinics and proven, by our own research, as highlyneuroprotective and promoters of functional recovery. The finalgoal is to elucidate the molecular and cellular mechanisms underl-ying neural damage and develop novel, clinically feasible repairtherapies.

Drs. Xavier Navarro and Rubén López-Valés (Group forNeuroplasticity and Regeneration, Department of Cell Biology,

Physiology and Immunology,Autonomous University of Bar-celona; Spain). Dr. Ernest Are-nas (Molecular NeurobiologyUnit, Medical Biochemistry andBiophysics Department, Karo-linska Institute; Sweden). Drs.Guido Fumagalli, Ilaria Decimoand Franceso Bifari (Depart-ment of Clinical and Experi-mental Medicine andDepartment of Medicine andPublic Health, University of Ve-rona; Italy). Dr. Javier Díez(HISTOCELL, Biotech Com-pany specialized in Tissue Engi-neering and Cell Therapies;Spain). Consorcio NEURIMP:IK4-Tekniker e HISTOCELL(Basque country). ContiProPharma (Czech Republic).Vor-nia (Irland). Univer-sity of Sheffield andUniversity of Wes-tminster (UK).

The problem

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Photo: Carlos Monroy(Left to right) Alfredo Maqueda, Marta Fernández, Carlos González, F. Javier Rodríguez, Pau González, Sandra Vázquez and Virginia Pérez.

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The group video

Developmental Neurobiology (GNDe)

Main investigator


Our main research line focuses on the study of oligodendrocy-tes, the cells that form the myelin sheath around nerve fibers and facili-tate the nerve impulse transmission. These cells die in multiple sclerosis(MS) and other demyelinating diseases.

We study the basis of myelination and demyelination to iden-tify potential biomarkers that better diagnose multiple sclerosis (the se-cond leading cause of paraplegia after different traumas) and to advancethe neural repair therapy of the disease. We are especially interested inoligodendrocyte precursors (OPCs) in the adult central nervous system(CNS), comprising 3-8% of total cells thereof.

Our experimental work, employing samples from patientswith MS and animal models of the disease, addresses different molecularinteractions underlying the development of oligodendrocytes and mye-lination, as well as in vitro studies of OPCs and other relevant cell types.

The oligodendrogliogenesis and myelination are still poorlyunderstood processes despite their direct implications in congenital dem-yelinating diseases and indirect implications in other pathologies of thiskind. Certain factors, as extracelular matrix associated glycoproteinanosmin-1, are important players in the oligodendrogliogenesis and alsoin MS. The OPCs generated in different regions of the neural tube donot behave equally, hence the importance of knowing their normalphysiology, studying their behavior under a pathological condition andseeking a cure for it.

The latter presents the ultimate goal of our research with theOPCs found in the adult brain. Contrary to an earlier notion, that theseOPCs are similar to those populating the CNS during embryonic andpostnatal development, a growing body of evidence demonstrates theirdifferences in both biological characteristics and potential.

We study demyelinating pathology in mice, by inducing ex-perimental autoimmune encephalomyelitis (EAE), and in patients´ sam-ples, where we can confirm how the pathology actually unfolds inhuman brain. Additionally, we analyze the cerebrospinal fluid of patientsin order to detect components that may help us diagnose earlier the di-sease and differentiate between groups of patients so as to to predict itsoutcomes and determine possible treatments.

We have developed a protocol for efficient sepa-ration of OPCs from adult animal brains that is

also applicable to neurosurgical samples from patients and, thanks towhich, we can now identify different molecules with the functions cha-racteristic of OPCs (i.e. survival, proliferation, differentiation into mye-linating oligodendrocytes). Using samples´from patients, we have alsoestablished that some of these molecules (e.g. anosmin-1) are specificto lesions in which there is no spontaneous remyelination, while othermolecules (e.g. FGF-2) are specific to lesions in which spontataneousremyelination does occurr. Concordantly, this knowledge will help im-prove the disease diagnostic by identifying patient subtypes and specifictargets for potential reparative therapies.

We have also shown that myeloid suppressor cells (MDSCs)enter from the blood stream to the nervous parenchyma in response toinflammatory demyelinating damage. Unlike in other pathologies (e.g.cancer, infections), the MDSCs in MS limit the inflammation, thus li-mitting the damage, which ultimately converts them into a potential the-rapeutic target.

Besides different Spanish groups and networks, we colla-borate with Roland Martin and Mireia Sospedra (University HospitalZürich, Switzerland), Ferdinando Rossi (University of Torino, Italy),Benedikt Böerninger (University of Mainz, Germany) and Bernardand Catherine Lubetzki (AFTA, Institut du Cerveau et de la Moelle,Paris, France).

The problem

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Photo: Carlos Monroy(Left to right) Carolina Melero, Sonia Nocera, Diego Clemente,

Isabel Machín, Iris Sánchez, Fernando de Castro, Arturo González, Rafael Lebrón and Blanca Rodríguez

Progress

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The group video

Membrane Biology and Axonal Repair

Main investigator

Following certain injuries and/or diseases that affectthe central nervous system (CNS) axons are unable to regenerate,which in turn hinders its functional recovery. The cell membraneis at the core of this problem because the broken membraneallows the entry of harmful external factors into the neuron thatmay even kill it. Furthermore, immediately after sealing, themembrane of the affected axons contacts injured nervous tissuethat inhibits axonal growth and the formation of new synapticcontacts. Both the sealing and regeneration of injured axons di-rectly depend on the correct function of the cell membrane.

Our laboratory investigates the role cell membraneplays in axon formation, growth and regeneration. We aim to un-derstand how various injuries to the CNS alter the membrane or-ganization and devise strategies to revert their effects, hencestimulating axonal regeneration and functional recovery. To reach

our goals we modify and analyze membrane components (i.e. as-sociated lipids, proteins and sugars) at molecular or cellular level,as well as in animal models of nerve injury.

We have demonstrated that the increased activity of themembrane enzyme Neu3 makes the CNS axons regenerate invitro. We have also shown that in spontaneously regenerating in-juries of the peripheral nervous system the activity of Neu3 in-creases with the injury, this increase being considered asnecessary for the recovery. By using cell and gene therapy in ani-mal models, we are currently adapting this enzymatic activity toimprove the CNS recovery from injuries that normally do not re-generate spontaneously (e.g. spinal cord injuries).

Furthermore, we have demonstrated that galectins, agroup of proteins that binds to certain classes of polysaccharidesin neurons, play an important role in axonal function. For exam-ple the phosphorylated form of galectin-3 regulates axonal bran-ching, while galectin-4 determines the transport of glycoproteins

in axons and regulates their myelination. Theseand other similar results along these lines pointto galectins as molecules with a high potentialfor enhancing neural regeneration.

Naturally, we could not have advanced ourresearch without establishing collaborationswith other scientists and institutions. Among re-levant examples are internal collaborations withDrs. Juan de los Reyes Aguilar and Antonio Oli-viero and external collaborations with Dr. TaekoMiyagi (Miyagi Prefectural Cancer Center, Mi-yagi, Japan), Dr. James Fawcett (Brain RepairCenter, Cambridge, En-gland), Prof. Dr. Hans-Jo-achim Gabius (Univ. ofMunich, Germany) and Dr.Carlos Dotti (CBMSO-CSIC, Madrid).

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Photo: Carlos Monroy(Left to right) José Abad Rodríguez, Eider Goiriena Foruria, Alonso Higuero Romero, María Peñas de la Iglesia and Natalia Díes Revuelta.


Collaborations

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The group video

Vascular Pathophysiology


Acute forms of various cardiovascular diseases like acute co-ronary syndrome (ACS), stroke, coronary artery disease and valvular di-sease are the leading cause of death in developed countries and also showa growing prevalence in developing countries. The main problem withthese diseases is their slow and silent progression during decades with noobvious symptoms until the time of the event that is harmful to the patientand also implies a high socioeconomic cost. This leaves not only a widewindow for early diagnostic, but also for the evolution of risks for deve-loping any of these complications, as currently there are no indicators orpredictors that allow detection of underlying pathophysiological processesprior to their clinical manifestation.

Our laboratory conducts translational research based on a mul-tidisciplinary and unbiased approach that characterizes omic strategies.We use human samples without pre-selected target molecules (i.e. all thoseproteins and metabolites whose expression levels are affected incipientlyas a whole) that enables us to: 1) get better understanding of cardiovasculardiseases at the molecular level, 2) stratify risk level correctly from theomic profiles (proteins, metabolites) obtained by identifying a specificmolecular fingerprint associated with increased cardiovascular risk, and3) find indicators or predictors that allow detection of pathophysiologicalprocesses that precede the clinical manifestation of the disease.

Our group has been working in the area of vascular metabolo-mics and proteomics for more than 10 years and presently has a prominentrole both nationally and internationally.

We have approached the study of circulating monocytes in in-dividuals with ACS as an alternative source of biomarkers and describedfor the first time, that these cells express a characteristic profile associatedwith the ACS. Moreover, within the pathology of atherosclerosis, we havedeveloped a laser microdissection and pressure catapulting methodologyin combination with proteomic strategies that permit isolation of arteriallayers (intima and media) where the main mechanisms of atheroma de-velopment are located. This has allowed us to compare the protein profiles

of both layers in coronary arteries with and withoutplaque, as well as in the radial artery as a control,identifying differential proteins with a key role in thedisease. We have also contributed to the study of thepathophysiology of degenerative aortic stenosis by

means of various proteomic techniques and are studying other vasculardiseases, like stroke, as well as major risk factors for cardiovascular dise-ases, such as hypertension. At present we are applying our knowledge inthe field of -omics to other pathologies, as those related to spinal cord in-jury (Mapfre project).

In summary, our research so far has resulted in more than 50articles published in refereed journals, four PhD. thesis (Fernando de laCuesta, Tatiana Martin Rojas, Carlos M. Laborde, Laura Mouriño), fourMSc. thesis and three patents.

Last but not least, our group forms a part of the Human Prote-ome Project in Madrid-Toledo Node, as well as of the Cardiovascular Re-search Network (ICN), the ProteoRed-ISCIII and the governing body ofthe Spanish Society of Proteomics.

Our collaborations with other scientists or research institutionsinclude: The Human Proteome Project, with participating laboratories dis-tributed throughout the world (e.g. Korea, Russia, Iran, Japan, Canada,the United States, China, etc.), Dr. Pedro Moreno (Mount Sinai Hospital,New York, USA), Drs. Schmitt-Kopplin and Sara Forcisi (Helmholtz Zen-trum München, Germany), Dr. Ruilope (Hospital 12 de Octubre, Madrid,Spain), Drs. Fernando Vivanco and Gloria Alvarez Llamas (IIS-JimenezDiaz Foundation, Madrid, Spain), Drs. Miguel Rivera and Esther RosellóLletí (Hospital la Fe, Valencia, Spain), Drs. Juan Antonio López and JesusVázquez (CNIC, Madrid, Spain), Dr. Pedro Luis Sanchez (SalamancaUniversity Hospital, Salamanca, Spain), Dr. Ángel García (University ofSantiago de Compostela, Santiago de Compostela, Spain), Dr. FelixElorzta (CIC bioGUNE, Blibao, Spain), Drs. Joseph Moreu and CarlosMarsal (Toledo Hospital Complex, Toledo, Spain), Dr. Antonio Oliviero(National Hospital for Paraplegics, Toledo, Spain).

The problem

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Progress

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Photo: Carlos Monroy(Left to right) Montse Baldán, Tamara Sastre, Rafael Moreno, Laura Mouriño,

Luis R. Padial, Maria Eugenia González and Fernando de la Cuesta.

The group video

Main investigators

The fundamental problem that we aretrying to solve is regeneration following spinal cordinjury and in neurodegenerative diseases. These pa-thologies cause persistent deficits due to the failureof mature neurons to be replaced or, when they sur-vive, to regenerate their axons. To address thisissue it is necessary, first, to support cellular survi-val and, second, to induce axonal growth andsynaptic plasticity. In order to intervene therapeu-tically we need to better understand the endogenousmechanisms of compensation and regeneration inthe central nervous system (CNS).

In the peripheral nervous system regenera-tion is already possible because peripheral nervesfrom the same individual can be transplanted (au-tologous nerve grafts). However, since this appro-ach has several disadvantages, including sensorydeficits at the donor site, the challenge consists indeveloping alternatives to replace the transplanta-tion of autologous nerves.

We are focusing on two lines of research:First, we are using a neurochemical appro-

ach to control the glial scar, modulate neuroinflam-mation and promote axonal regeneration andsynaptic plasticity. Specifically, we focus on signa-ling cascades of NR/RXR nuclear receptors, whichinclude those of vitamins A and D, and the regula-tion of Rho-GTPases. We are investigating their en-dogenous functions after spinal cord lesion and inperipheral nerve regeneration.

The second line of research has the objec-tive to construct a cell-free, artificial implant toserve as a bridge for the repair of peripheral nerves.Our guidance structures for cell migration and axo-nal growth are based on synthetic polymers that arefunctionalized with proteins and peptides from the

extracellular matrix. In parallel, such growth subs-trates are used for cellular transplants. We are stud-ying novel release mechanisms for the localadministration of pharmaceutics in the nervoussystem.

We discovered that retinoic acid, the biolo-gically active derivative of vitamin A which activa-tes nuclear receptors, is involved in physiologicalrepair mechanisms after lesions of peripheral nervesand of the spinal cord. At the cellular and molecularlevel, we have characterized the anti-inflammatoryand pro-regenerative activity of nuclear receptoragonists and Rho-GTPases. With the goal of develo-ping artificial implants for nerve regeneration, wepioneered the technique of electrospinning to pro-duce orientated polymer fibers as guidance structu-res for axonal growth. Using organic chemistry weimproved methods to give artificial growth substra-tes biological functions.

Our international collaborations include re-search groups in Germany (Gary Brook, Katrin Bui-Göbbles, RWTH Aachen), the United Kingdom(Peter McCaffery, University of Aberdeen), the USA(José de la Fuente, Oklahoma State University) andSpain (Alfonso Fernández-Mayoralas and LeoncioGarrido, CSIC, Madrid). Biomaterial research andchemical synthesis are carried out in cooperationwith biotech companies.

Jörg Mey holds a professor positionat RWTH Aachen University, Germany (Apl.Professor), and is faculty member of theSchool of Mental Health and Neuroscienceof Maastricht University, Netherlands.

Nerve Regeneration and Neurochemistry

Main investigators


The problem

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@HNParaplejicos

The group video


The National Hospital for Paraplegics also counts with several facilities that providetechnical support to the basic research unit. They were founded with the objective of pro-viding professional technical assistance and information sharing for the researchers and toassure the maximum efficiency of the available equipment. Each facility counts with thelatest equipment, installations and highly qualified personnel that provide support notonly to in-home research groups, but also to other public and private companies in the area.

José Ángel Rodríguez Javier Mazarío

he facility counts with the ultimate generation ofequipment for traditional and fluorescence microscopy,

multicolor immunofluorescence imaging and for a va-riety of live cell and in-tissue studies. Available equipmentincludes: microscopes for capturing videos of live cells, lasercapture microdissector, two confocal microscopes (one

equipped for work with live tissue samples and the other onewith automatic capture of images and their analysis i.e. HighContent Screening), as well as computer programs for pre-paration and analysis typical of neuroscience research (e.g.NewCAST, Neurolucida, ImageJ). We also count with onelaser scanning electron microscope that allows for more ad-vanced and detailed structural studies.

The facility routinely acquires high magnificationimages of micro- and macro structures (macroimages of tis-sue sections) that require image tilting and stitching, per-forms studies of cell migration and co-localization,stereological studies, micro-dissection of tissue regions forRNA and protein analysis, processing and analysis of digitalimages and other microscopy related techniques.

low cytometry presents a special form of laser-basedmulticolor microscopy in which prelabeled cells, sus-pended in a stream of fluid, are passed by an electronic

detection device whereby simultaneous multiparametricmeasurements are taken for later quantification of biochemi-cal, phenotypical and/or molecular properties of individualcells. The analysis is performed at the speed of up to thou-sands of cells per second, which in turn provides the data ofhigh statistical reliability.

Available equipment includes one benchtop cellanalyzer, FACS Canto II, which allows for multiparametricanalysis of complex cellular populations and one benchtopcell sorter FACS Aria (BD Bioscience) that provides highvelocity physical separation of specific cellular populationsfor their later use in biochemical and molecular assays, ce-llular differentiation or as transplants in animal models.

The facility offers services such as sample prepa-ration and separation, data acquisition and analysis, as wellas professional assistance in experimental design, protocoloptimization and up-to-date information about the use of newtechniques and reagents.

Virginia Vila del Sol

Cytometry

Microscopy and image analysis

@HNParaplejicos

Proteomics core facility

he facility is focused on searching for new and bet-ter experimental designs, protocol optimization

and implementation of the latest knowledge and

technology in the field of proteomics. It offers supportnot only to the hospital´s researchers but also to externalusers from other regional institutions. Proteomics tech-niques provide a highly valuable data source for basicand clinical research alike.

The facility routinely performs protein identi-fication and characterization by MALDI TOF/TOF; pro-tein separation and differentiation by 2-dimensional gelelectrophoresis 2D-DIGE and screening for possible bio-markers by MRM.

Gemma BarrosoAlba González


he facility is dedicated to high standards breeding,housing and management of laboratory animals. Our

installations include several animal housing rooms, withthe total capacity for 2000 rodents, surgical rooms, as

well as especially equipped rooms for behavioral and kine-matics studies.

The facility also provides teaching and trainingcourses on animal care and surgery for the research personnel,while ensuring fundamental principles of bioethics, offering

alternatives to animal experimentation, as well as refinementand optimization of experimental protocols.

Enrique Páramo Rosel

Animal housing facility

The hospital also counts with state-of-the art MRI facility (led by Jose Florensa)shared by the research and clinics and an impending cell culture facility, led by MonicaCarballo. The latter will provide professional assistance to the research part of the hos-pital and allow for the development of new cell culture protocols and cellular experi-mentation adjusted to meet specific needs of individual projects.

The personnel is also committed to training and formation of research- and he-althcare professionals, as well as collaborating with the local community on variouseducational activities.

@HNParaplejicos

FENNSI Group


Main investigator

Spinal cord disorders frequently result in some incurable im-pairment. In general, patients with complete spinal cord injuries(SCI)recover very little of lost functions while patients with incomplete in-juries achieve more functional recovery. Some patients that are initiallyassessed as having complete injury may be later reclassified as havingincomplete injury.

The main problems we aim to solve are: improving evalua-tion of spinal cord injured patients in the early and chronic stages of theinjury; and addressing the lack of available treatments (more so thanrehabilitation procedures) useful for improving motor functions in spi-nal cord injury patients.

The central nervous system (CNS) is a very complex systemwhere different parts perform distinct functions. Majority of drugs com-monly used for treating CNS disorders, including spinal cord disorders,have neuroactive properties and even though we would prefer them toact only in a very restricted area of the CNS, that is not the case. Na-mely, once a drug has entered the CNS it usually exerts beneficial ef-fects in a restricted part of the CNS but at the same time producesvarious unwanted effects in most of the remaining brain and spinal cord.

The application of electric currents or magnetic fields overor deep inside the brain can be used to selectively target a specific area,thus producing desired therapeutic effect. These techniques are knownas brain stimulation or brain neuromodulation techniques. When electriccurrents or magnetic fields are applied transcranially the technique isreferred to as non-invasive. In line with this, our main goals are: to findbetter non-invasive neuromodulation strategies and to improve the cli-nical application of non-invasive neuromodulation techniques in treat-ment of CNS disorders and spinal cord injury.

SCI clinical trials (GH, CB1 Antagonists). The SCI has nocure. Rehabilitation improves only some clinical signs related to affec-ted motor functions. Thus, we are testing different drugs to improvethese functions, as an add-on therapy to neurorehabilitation. Humangrowth hormone and CB1 antagonists/inverse agonists are the molecu-

les we think may be useful for improvingmotor functions in incomplete spinal cord in-jury patients.

Treatment of pain in SCI using non in-vasive brain stimulation (NIBS) approach.Neuropathic pain is referred to as the most

important symptom in about 10% of SCI patients. Although drug treat-ments have improved significantly in the last decade, they are often notwell tolerated (or effective) in a great number of patients. NIBS offersa simple, inexpensive and safe treatment option.

Psychoneurophysiology and neuroradiology of SCI.Hand Functions and Cognitive functions in SCI. Transcranial static magnetic field stimulation as a new non-

invasive neuromodulation strategy. Optimization of tDCS using NIRS. This approach will allow

us to determine an individualized treatment and a follow-up of the bio-logical effects of tDCS.

Improvement of brain computer inteface (BCI) strategy usingNIBS (tDCS). The main goal is to speed-up the learning process in theBCI users by improving the “informative” signals detection and deco-ding.

UCL, London, UK; EPFL, Lausanne, Switzerland; DrexelUniversity, Philadelphia, US; Centro de Tecnología Biomédica, Madrid,Spain; Universidad A Coruña, A Coruña, Spain.

The problem

Collaborations

Photo: Carlos Monroy(Left to right) Elena Lozano, Simona Sabbarese, Vanesa Soto,

Laura Mordillo, Michele Dileone, Yolanda Pérez and Antonio Oliviero

The Research

@HNParaplejicos

The group video

Biomechanics and Technical Aids

Main investigator


Spinal cord injury (SCI) produces severe movement disor-ders that usually require technical aid to compensate for theimpairedmotor function. Biomechanics is a multidisciplinary field of knowledgethat not only provides quantitative information useful to physicians,while deciding the best therapy for a patient, but also serves as a vehiclefor implementing new technologies that improve the rehabilitation pro-cess and compensate for produced motor deficits in people with SCI.

Our research activity is focused on motion analysis and eva-luation of technical aids for SCI patients. Thus, we use motion analysis(gait, manual wheelchair propulsion, upper limbs movements in every-day activities) as an aid in clinical diagnostic-decision making processand as a starting point in the design and evaluation of robotic devices(i.e. robotic exoskeletons). Moreover, motion analysis serves to us asa foundation in the development of virtual reality applications used forrehabilitating various limb motor deficits and provides us with the kno-wledge regarding the influence of these new technologies on the me-chanisms of neuroplasticity.

In the process we rely on the technical aids evaluation ser-vices (as pressure mapping, physiological assessment of tissue at highrisk for pain, functional assessment wheelchair) which we also offer tomanufacturers, distributors and the field related companies.

Our group has defined gait patterns in specific syndromesof incomplete SCI, such as Central cord and Brown-Sequard syndro-mes. We have also developed our own model for studying the upperlimb and implemented the technology required to analyze the ergono-mics of manual wheelchair propulsion. This in turn allowed us to ac-quire relevant biomechanical data on how patients with different levelsof SCI perform manual wheelchair propulsion. Our group has also con-tributed to the development and clinical evaluation of a line of hindlimb exoskeletons whose function can be based on the activation ofjoint actuators (Ex H2), on the combined action of the actuators andfunctional electrical stimulation (FES) of the residual musculature(hybrid performance), or on their coupling to the partial weight supportsystems (Hybrid). Furthermore, we have participated in the develop-ment of an intelligent sitting system based on the detected risk valuesfor developing pressure ulcers, which automatically generates repair

strategies (PUMA project). Finally, our laboratory hascontributed to the development of a virtual reality systemfor the upper limb motor rehabilitation (Toyra). This de-vice includes a new version of Kinect software (Micro-soft) as a motion capture system to be applied inTV-rehabilitation platforms.

We have developed collaborations with leadinginstitutions and scientists at the national and internationallevel, among them Rory A. Cooper (Human EngineeringResearch Laboratories, University of Pittsburgh, USA),Meten Akay (Department of Biomedical Engineering,University of Houston, USA), JoséLuis Pons (Bioengineering Group,CSIC, Spain), the Institute of Bio-mechanics (Valencia, Spain) andthe company Indra Sistems, Spain.

Photo: Carlos Monroy(Upper left to right) Vicente Lozano, Soraya Pérez, Elisa Piñuela, Antonio del Ama, Ana delos Reyes, Ángel Gil and Enrique Pérez.

The problem

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@HNParaplejicos

The group video

Gait Re-education and Functional recovery


Main investigator

Spinal cord injury is a pathology that affects different areasof patient's life such as the mobility, sensation, bowel and bladder func-tion as well as his sexual ability.

Depending on its severity, the injury may affect pelvic organs,lower extremities, trunk, abdomen and upper extremities. Furthermore,secondary complications such as spasticity and pain, that usually ac-company the injury, may significantly delay, as well as interfere withthe rehabilitation process.

The group includes physicians specialized in rehabilitationmedicine and physiotherapists specialized in robotic gait-training system(Locomat). Our daily alternation between the work with patients andclinical research has opened several research lines:

The study of different treatments for optimization of gait re-covery in persons with neurological disorders, with two research pro-jects completed and a new one pending.

Defining protocols for a better evaluation of treatments ap-plied in daily clinical practice.

New treatments that are incorporated daily at the clinic arein need of detailed assessments, hence it is important to develop newsystems that will allow for a precise evaluation of their outcomes.

The study of medical complications in people with spinalcord injury such as phonation (or lack of it), pain, spasticity and vesico-uretheral dysfunction.

In the future we plan to incorporate new types of treatmentsacting directly on the brain and to follow their effects on patients’ func-tional recovery. Moreover, we will also incorporate the Isokinetics unitin order to improve the accuracy of analytical measurements and incre-ase benefits of presently used muscle treatments.

Through the research we learned that incomplete spinal cordinjury patients develop more stamina and fati-gue resistance during gait when trained with theLokomat robotic system

In other lines of research, as the one re-garding the vesico-urethral dysfunction, wehave learned that applying prophylactic antibio-

tics prior to the change of indwelling urinary catheter and initial bladderre-training decreases significantly urinary tract infections.

The group collaborates with the European Multicenter Studyon Spinal Cord Injury with the goal of creating a European database oftraumatic spinal cord injuries. It also collaborates in a randomized, tri-ple-blind, clinical trial on the efficacy and safety of growth hormone(GH) use in patients with spinal cord injury, which is currently beingconducted at the HNP

Together with the Biomechanics Unit of the HNP, the groupparticipates in projects featuring comparative analysis of clinical andbiomechanical parameters of the gait in patients with spinal cord hemi-section and Central cord syndrome. Our group is also participates in amulticenter project called "Advanced Systems EEF and UMI for de-veloping soft-robots in the field of rehabilitation robotics: REHABOTII project.", coordinated by the Institute of Industrial Automation andthe Institute of Biomechanics from Valencia, Finally, the group colla-borates on a project called REHABILITA-Disruptive technologies forthe rehabilitation of the future within the national strategic program fortechnical research consortia (CENIT-e) of the Ministry of Science andInnovation.

The problem

Collaborations

The Research

Photo: Carlos Monroy(Left to right) Silvia Ceruelo, Francisco Talavera, Rosa Casado,

Ramiro Palazón, Mónica Alcobendas, Ana Esclarín and Guillermo Pérez.

Progress

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The group video

Assisted reproduction

Main investigator


People who suffer spinal cord injury (SCI) experience chan-ges in their sexual response and fertility. These changes are due tophysical alterations caused by the spinal cord damage, as well as dueto psychogenic component present in these persons who have to adaptto a different model of sexuality from the one they had prior to the in-jury.

Our research unit studies the alterations in sexual responses,which occur after spinal cord injury in both men and women. In males,our research is centered on erectile dysfunction and its possible treat-ments (e.g. oral, intracavernous, intraurethral, etc), as well as on inquiryinto their fertility that is naturally diminished. Similarly, in female pa-tients we study problems they experience after SCI to help them main-tain satisfactory sexual relations and to provide them with thepregnancy and childbirth recommendations.

On one hand, our research aims to evaluate patients respon-ses to various treatments for erectile dysfunction as PDE inhibitors (Sil-denafil, Vardenafil, Tadalafil), intracavernous (e.g. Prostaglandin E1,Papaverine) or intraurethral drugs, using the satisfaction rating scale of

their sexual activity. On the other hand, we conduct studies on fertilityand its evolution in men with SCI and possible applications of differenttechniques for achieving semen production (e.g. vibro-stimulation,electro ejaculation) either alone or in combination with drugs asPhysostigmine or Midodrine. Finally, we study different techniques ofassisted reproduction to ensure the most suitable treatment for each per-son and its type of SCI.

By employing the anatomy and pathology of testicles in menwith complete SCI (ASIA A), we have studied the change of sperma-togenesis in the acute phase of SCI that is characteristic of different in-jury levels, the latter being established by means ofelectro-neurophysiological and clinical studies.

We have also evaluated different treatments for erectiledysfunction by using objective measurement records (RigiScan plus)and evaluation scales of achieved erectile responses. Thus, we have as-sessed the degree of satisfaction with their sexual activity (in men witherectile dysfunction receiving drug treatment) by applying satisfactionrating scales to their own and their partner´s activity.

We have also conducted a descriptive study of the results ofdifferent fertility techniques performed at the Unit (Assisted Coupleand Home Insemination) and improved planning of measures to betaken in the course of pregnancy and childbirth in women with SCI.

We are currently developing a research project regarding al-terations of the sexual function in women with spinal cord injuries andits usefulness in the assessment of physical, bodily damage.

Our work has been performed in collaboration with differentcenters, including Spanish and foreign universities. We have a closecollaboration with Dr. Antonio Sanchez Ramos (former head of the Re-habilitation Service HNP and the chief of the Sexuality Unit at theFoundation for SCI of Madrid), Professor Manuel Mas (PhysiologyProfessor at the La Laguna University, SantaCruz de Tenerife, CESEX group), Dr. AntonioOliviero (group FENNSI at the National Hospitalfor Paraplegics), Professor Giuliano (RaymondPoincare Hospital, Garches, France) and Dr.Martin Francisco (Hospital Virgen de la Salud).

The problem

Collaborations

The Research

Progress

Photo: Carlos Monroy(Left to right) Ana Galán, Eduardo Vargas, Rosi Arriero and Guadalupe Sánchez.

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The group video

Orthopedic Surgery and Traumatology department


Main investigator

Kyphosis presents a forwardrounding of the spine and usually re-fers to an exaggerated rounding of theupper back (i.e. thoracic vertebrae).The principal problem that our groupis trying to resolve is the relationshipbetween the degree of kyphotic angu-lar deformity (i.e. kyphotic angle),consequent spinal lesion and the pre-sence of mechanical pain in patientswho suffered vertebral fractures.

To achieve this objective ourgroup has undertaken a clinical studyin which we examined radiographs of700 patients treated at the NationalHospital for Paraplegics and analyzeda series of pain- and disability-relatedinquiries they were asked to complete.

Our study still remains to becompleted but, based on the data co-llected so far and contrary to the prevailing field notion, we

believe that the degree of kyphoticangular deformity (i.e. kyphoticangle) as an isolated value does notcorrelate with the presence (or ab-sence) of pain in these patients.

Our group collaborates with the Spanish Networkof Researchers in the Back Ailments and with the AOSpineEurope, the international community of spine care profes-sionals with the headquarters located in Duebendorf, Swit-zerland.

The problem

The Research

Photo: Carlos Monroy(Left to right) Jesús de Juan and Andrés Barriga

Progress

Collaborations

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The group video

Functional Urology and Urodynamics

Main investigator


Clinical research in the field of functional Urologyfaces numerous challenges when it comes to patients with spi-nal cord injuries, one of them being vesico-urethral reflux thatfrequently causes renal failure and impacts on life expectancyof the lesioned. Fortunately, there are new and reliable diag-nostic tools, such as Ambulatory Urodynamics and Compu-terized Videourodynamics, as well as therapeutic approachesfor the identification of this pathology.

We investigate the difference between the conven-tional and Ambulatory Urodynamics with the objective of

compiling data, classifying and documenting differences inthe behavior of bladder sphincters. Additionally, we combineTeleurodynamics (i.e. a highly reliable long distance diagnos-tics) and Videourodynamics that allow us to conduct an indi-vidualized study of lower urinary tract in each case ofvesico-urethral reflux. Therefore, our research efforts and aspecific, personalized treatment for each patient translate di-rectly into a significant increase in patients´ life expectancy.

Our group has documented the existenceof various, unexpected signs in the behavior of lower urinarytract that depend on the lesion level. This discovery helped uscreate specific treatment protocols for each, individual vesico-

urethral reflux characteristicof the lesion level, documen-ting in total six distinct beha-vioral patterns.

We have establishedimportant collaborations withother scientists and institu-tions in the field. Our grouphas been awarded numerousstipends and subventions fromthe national public (SpanishUrology Association and FIS)and private institutions as wellas from the International Con-tinence Society, throughwhich we lead theI n t e r n a t i o n a lGroup of Videou-rodynamics.

The problem

ProgressThe Research

Collaborations

Photo: Carlos Monroy(Left to right) Manuel de la Marta, Isabel del Cerro, Vicente Gandía, Manuel Esteban, Miguel Vírseda, Mª Eugenia del Castillo, Antonio Miguel López, Pilar Nombela and Ana Sánchez.

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The group video

ontrary to the world of globalized science, where infor-mation and funding flow freely, there is still a long wayto go to achieve globalization of human dignity for themost disadvantaged groups. One of these groups is par-ticularly close to our line of work and includes persons

with disabilities.With the above concept in mind, many of our professionals have

participated in executing and/or developing different internationalcooperation projects, some of which will be highlighted here:

The collection and delivery of wheelchairs and prosthetic equip-ment to war zones, as Afghanistan (Herat) and Bosnia, in collabo-ration with the Spanish Army; The treatment of spinal cord injuriesin victims of gunshot wounds from Libya; ́ ´Surgical brigade´´, for-med by our urologists, providing medical care for disadvantagedpopulations of Honduras (Tegucigalpa) and other Central Ameri-

can countries; Professional coo-peration program (includingdonations, volunteering andcounseling) with the Spinal In-jury Rehabilitation Center inNepal; Collaboration with theFoundation “Maestros de la su-pervivencia” in Colombia; Pro-fessional training inRehabilitation medicine for aphysician Sorab Hussein froma Hospital in Bangladesh;

Financial aid and counselingprogram for the AssociationHANAN of Morocco; Collabo-ration with the Foundation Vi-

cente Ferrer on the project ‘’Fisios Mundi’’ in India, or varioushumanitarian initiatives in countries as Senegal, Ethiopia and Angolaare only some of the examples depicted in the map.

Following the motto ‘’Open to the World’’, starting with the ’92Olympic games in Barcelona to 2008 in Beijing, to 2012 in London andwith great expectations for the upcoming gamesin Brazil, the HNP has served as a breedingground for some of the best international athletesin Paralympic sports. Some of their stories arecaptured in the book ‘’Beyond Sport’’.

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Infomédula Nº33 (inglés)

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Transcript of Infomédula Nº33 (inglés)