DREXEL UNIVERSITY COLLEGE OF MEDICINE

The Edward Jekkal Muscular Dystrophy Research Fellowship

PREAMBLE

The Edward Jekkal Muscular Dystrophy Research Fellowship is designed to strengthen the training of senior postdoctoral students or young research faculty members interested in neuromuscular disease research. The Fellowship is a one year award with the possibility of a second year of funding. Application forms are available in pdf format or msword format

The Fellowship is funded through the generosity of the Muscular Dystrophy Association and the late Edward Jekkal, an AT&T mechanical designer who lived in Bucks County, Pennsylvania. Mr. Jekkal is remembered for his kindness and generosity and the talent that enabled him to design assistive devices to compensate for disabilities.

Creation of the fellowship was furthered by Leonard S. Jacob, M.D., Ph.D., a MCP alumnus and who was a Board of Trustees member and a friend of the Jekkal family. The Jekkal estate and the MDA contributed to establish the fellowship, with a matching contribution from Drexel University.

Drexel University will provide the training environment that will assist the Fellow in establishing an independent multi-disciplinary research program. Interested applicants will be expected to work with a primary sponsor at Drexel University for the purpose of establishing a host laboratory and developing the proposal. Junior research faculty at Drexel University can submit an independent application. The typical successful candidate will already have completed several years of postdoctoral research training about to move into a faculty position and can also be junior faculty. Special consideration will also be given to M.D’s. who have completed their residency training and will be in the position to plan and execute a research program while receiving input and guidance from a core group of faculty, in addition to his/her primary sponsor.

This core training group will be drawn from faculty having demonstrated strengths in the physiology and pathology of neuromuscular and related diseases, molecular biology of transmitter receptors and ion channels, regulation of contractile activity in muscles, and the structural organization and regenerative capacity of neurons. These faculty members represent the departments of Neurobiology and Anatomy, Pharmacology, Neurology, Microbiology and Immunology at Drexel University. The sponsor will be responsible for providing the primary training and the host laboratory.

Advisory Committee

Itzhak Fischer, Ph.D., Chair

Leonard Jacob, M.D., Ph.D.

Peter Baas, Ph.D.

John Houle, Ph.D.

Alan Tessler, M.D.

___________________________

Training Faculty

Elizabeth Blankenhorn, Ph.D.

Jeffrey Deitch, Ph.D.

Gianluca Gallo, Ph.D.

Simon Giszter, Ph.D.

Terry Heiman-Patterson, M.D.

John Houle, Ph.D.

Michel Lemay, Ph.D.

Gordon Lutz, Ph.D.

Young Jin Son, Ph.D.

 

Jekkal Research Fellowship

Faculty Research Descriptions

Elizabeth Blankenhorn, Ph.D. –- Microbiology and Immunology

Projects: We are conducting several studies to examine the genetic control of susceptibility to experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, in mice and in rats (right). A second project is to map both EAE-susceptibility and diabetes-susceptibility loci on the LEW rat genetic background, and to understand the role of the TCR haplotypes in severity of disease. We are extending our finding that diabetes in the BB rat strain is controlled by a QTL that we discovered on chromosome 4. Positional cloning of this QTL is underway, and we were excited to discover that this gene is also critical for the development of Type I diabetes induced by exposure to a virus as well. In recent years, we have applied genetic analyses to study susceptibility to retroviral infections, to amyotrophic lateral sclerosis (ALS), and to retrovirally induced lymphomas in mice. Finally, in collaboration with the Wistar Institute, we are mapping wound healing genes in several large crosses to confirm our original mapping of six QTL associated with the trait of wound healing/regeneration, and to understand the significant sexual dimorphism in the genetic control of this trait.

Methods: Immunogenetic models in the lab include both rat and mouse models of multiple sclerosis and diabetes, wound healing, ALS and other complex traits. We use genetic linkage to first identify the position of the gene that regulates that trait. The inheritance of marker alleles is compared (“linked”) to the inheritance of the phenotype and a preliminary assignment of the location of incidence and quantitative trait loci (QTL) is made. The QTL are confirmed in subsequent crosses, or are fixed in the genome by selective breeding, for the purpose of positional cloning and identification of the disease gene itself. We typically breed animals to express the susceptible allele of the QTL only on the resistant background, to determine if it can act in isolation to create a phenotype related to the complex trait.
The genetic analyses are combined with traditional immunological assays to assess immune function, and with real-time PCR and array techniques to assess gene expression. When successful, we are able to map the disease gene, identify it, and determine the important features of each allele that contribute to the different manifestation of the disease state. In this way we truly define “gene8 allele8 protein8 function” relationships for important disease entities.

Relevant Publications

Alexander GM, Erwin KL, Byers N, Deitch JS, Augelli BJ, Blankenhorn EP, Heiman-Patterson TD. Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res Mol Brain Res. 130:7-15. 2004

Polanczyk M, Yellayi S, Zamora A, Subramanian S, Tovey M, Vandenbark AA, Offner H, Zachary JF, Fillmore PD, Blankenhorn EP, Gustafsson JA, Teuscher C. Estrogen receptor-1 and -2 regulate the severity of clinical experimental allergic encephalomyelitis in male mice. Am J Pathol. 164:1915-24. 2004

Blankenhorn EP, Rodemich L, Martin-Fernandez C, Leif J, Greiner DL, Mordes JP. The rat diabetes susceptibility locus Iddm4 & at least one additional gene are required for autoimmune diabetes induced by viral infection. Diabetes 54:1233-7. 2005

Heiman-Patterson TD, Deitch JS, Blankenhorn EP, Erwin KL, Perreault MJ, Alexander BK, Byers N, Toman I, Alexander GM. Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS. J Neurol Sci.;236:1-7. 2005

Teuscher, C., R Noubade, K Spach, J Y. Bunn, P D. Fillmore, J F. Zachary, and E. P. Blankenhorn. Evidence That The Y-Chromosome Influences Experimental Allergic Encephalomyelitis in Male and Female Mice. Proc Natl Acad Sci USA. 23;103(21):8024-9. 2006

 

Jeffrey S. Deitch, Ph.D. –- Department of Neurology
Terry Heiman Patterson, M.D. –- Department of Neurology

Our lab uses a number of different approaches to study the mechanisms of motor neuron diseases and to search for potential therapeutics to degenerative diseases of the neuromuscular system. Our work uses the G93ASOD1 mouse model of amyotrophic lateral sclerosis (ALS).

The main research project involves mapping the genetic background of G93ASOD1 mice for genes that modify the onset and progression of disease. By breeding the transgenic mice onto different strain backgrounds, we have found that survival time varies by weeks depending on strain. Mice with the G93ASOD1 transgene bred onto a pure C57Bl6 background live almost two weeks longer than transgenic mice bred onto an SJL background. We have identified two loci highly correlated to length of disease. One gene of interest as a modifier of ALS expression is the survival motor neuron (SMN1) gene, which when mutated is a cause of spinal muscular atrophy. An SMN1 polymorphism has been identified risk factor for ALS in humans. How these two neuromuscular diseases are related and how one may modify the other is a major topic of investigation in the mapping studies.

A second line of work uses cell culture to investigate specific degenerative processes in motor neurons. Cell culture allows direct investigation of the degenerative processes in motor neurons and provides a faster method for screening compounds for potential therapeutic effects on motor neuron survival. Cultured neurons are examined for indicators of neurodegeneration, such as calcium dysregulation, mitochondrial dysfunction and oxidative stress. Other studies examine the whether neurotrophic factor signaling mechanisms are affected by the presence of the mutant SOD1 in the spinal cord cells.

We are also interested in understanding the behavior of stem cells injected into the spinal cords of the transgenic mice. We have developed a protocol for direct injection of mesenchymal stem cells into the mouse spinal cord and are pursuing projects to develop therapeutic applications for these and other stem cells.

Relevant Papers & Abstracts:

Alexander GM, Deitch JS, Seeburger JL, Del Valle L. and Heiman-Patterson, TD. (2000) Elevated cortical extracellular fluid glutamate in transgenic mice expressing human mutant (G93A) Cu/Zn superoxide dismutase. J. Neurochem., 74:1666-1673.

Deitch JS, Alexander GM, Del Valle L. and Heiman-Patterson, TD. GLT-1 glutamate transporter levels are unchanged in mice expressing G93A human mutant SOD1. J. Neurol. Sci., 193:117-126 (2002).

Alexander GM, Erwin KL, Byers N, Deitch JS, Augelli BJ, Blankenhorn EP, and Heiman-Patterson,TD. Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Mol. Brain Res., 130:7-15 (2004).

Heiman-Patterson TD, Deitch JS, Blankenhorn EP, Erwin KL, Perreault MJ, Alexander BK, Byers N, Toman I. and Alexander GM. (2005) Background and gender effects on survival in the TgN (SOD1-G93A)1Gur mouse model of ALS. J. Neurol. Sci., 236:1-7.

Heiman-Patterson T, Deitch J, Alexander GA, Erwins K, Byers N, Toman I, Blankenhorn EP. (2005) Genetic Loci Linked to Phenotype in the G93A SOD1 Mouse. Neurology 64S:A204-05.

Heiman-Patterson T, Rojas L, Yano R,  Myerson M, Deitch J, Alexander G, Cunningham T. Treatment of G93A SOD1 Tg mice with CHEC-9. 18th International Symposium on ALS/MND, Toronto, Dec 2007:SW307 (2007).

Muthusamy P, Patterson TH, Deitch JS, Deboo AF, Perrault MJ, Alexander GM. (2008) Interleukin 4 in ALS.  Neurology, 70 (Suppl 1):A195.

Sandu P, Alexander G, Deitch, JS, Myerson M, and Heiman-Patterson TD. Gender differences in survival of G93ASOD1 mice is not due to diferences in mutant SOD1 expresssion. Presented at the 18th International Symposium on ALS/MND, Birmingham, U.K., Nov. 2008.

Souayah N, Sharovetskaya A, Kurnellas MP, Myerson M, Deitch JS. and Elkabes, S. Reductions in motor unit number estimates (MUNE) precede motor neuron loss in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice. Exp. Neurol., 214:341-346 (2008).

 

Gianluca Gallo, Ph.D. –- Department of Neurobiology and Anatomy

Dr. Gallo's laboratory focuses on the cell biology of the neuronal cytoskeleton with two major areas of emphasis; (1) the extension and guidance of axons during development, and (2) the response of axons and dendrites to injury. The laboratory has been funded by the NIH and private foundations. In the laboratory we use a variety of approaches to address the research questions ranging from molecular and biochemical techniques to live imaging of the dynamics of the neuronal cytoskeleton. In recent years we have been expanding our research from in vitro model systems to in vivo systems through collaborative efforts with other departmental members (Dr. R. Raghupathi and Dr. J. Houle). Our basic modus operandi is to study the functions of the cytoskeleton using in vitro models systems in order to elucidate fundamental mechanisms, and then utilize the knowledge obtained from these basic cell biological investigations to develop mechanistic hypothesis regarding the response of neurons to injury in vivo. In the past this approach has led us to test the functions of myosin II in axon retraction in response to spinal cord injury (funded by the C. H. Neilsen Foundation and the PVA) and the role of localized microtubule disruptions in the impairment of axonal transport in the context of traumatic brain injury. Our current projects continue to investigate the roles of the cytoskeleton and its regulatory proteins and kinase/phosphatase systems. While continuing our work on the regulation of the cytoskeleton by neurotrophins and inhibitory guidance cues, we have recently also begun to address the roles of the Arp2/3 complex (a major nucleating system for actin filaments) and septins (a quasi-cytoskeletal cellular filament system) in axon extension and guidance. In addition, we have also begun to study the formation of dendritic fields and to test the role of myosin II in this phenomenon. In the future we plan on continuing with our work along the same general plan of extending our basic in vitro findings to models of in vivo neuronal injury and regeneration. The laboratory provides an excellent training environment through its in house use of multiple experimental approaches and strong collaborations with experts in the field of in vivo neuronal injury.

Relevant Publications

Kilinc D, Gallo G, Barbee KA. (2008) Mechanically-induced Membrane Poration Causes Axonal Beading and Localized Cytoskeletal Damage. Exp. Neurol. 212(2):422-30.
 
Gallo G. (2008) Semaphorin 3A Inhibits ERM Protein Phosphorylation in Growth Cone Filopodia Through Inactivation of PI3K. Developmental Neurobiology, 68(7):926-33.
 
Ketschek A, Jones SJ, Gallo G. (2007) Axon Extension in the Fast and Slow Lanes: Substratum Dependent Engagement of Myosin II Functions. Developmental Neurobiology. 67(10):1305-20.
 
Gallo G. (2006) RhoA-kinase Coordinates F-actin Organization and Myosin II Activity During Semaphorin-IIIA Induced Axon Retraction. J. Cell Sci. 119(16):3413-23.

Loudon R, Silver L, Yee HF Jr., Gallo G. (2006) RhoA-kinase and myosin II are required for the maintenance of growth cone polarity and guidance by nerve growth factor. J. Neurobiology. 66(8):847-867.

Gallo G. (2004) Myosin II activity is required for severing-induced axon retraction in vitro. Exp. Neurology 189(1):112-121.

Simon Giszter, Ph.D. –- Department of Neurobiology and Anatomy

The emphasis of my laboratory is on an understanding of the organization of spinal cord and how it helps the brain solve the degrees of freedom problem faced in motor control. We examine the neural and biomechanical modularity of motor output. We attack this using a basic science and comparative strategy, primarily using frogs, and we examine the impact of spinal modularity on corticospinal organization in the rodent and how it affects development and recovery of locomotor function after spinal cord injury. We also extend the approach for the development of brain-machine-interface and neurorobotic strategies, again using rodents.

1. Modularity in Spinal Cord

We use force-pattern, kinematic, electromyographic and neural recordings in frog spinal cord using reflex and voluntary frog behaviors.
Identification of Modularity We are able to identify modular elements by examining the statistical decomposition of motor patterns, the modular addition and deletion of muscle groups and force-patterns in reflex behaviors, and the neural clustering observed in recordings. Our data suggest that the behavioral and reflex repertoire of frogs may rest on the use of linear combinations of a small number of motor elements or primitives recruited by voluntary and pattern generator systems. In rats, cats and man similar results seem to hold. Our work in rodents also supports modularity in the hindlimb controls.
Neural Basis of Modularity Its is important to understand if a basic modularity in spinal cord is an emergent property of a network or optimization algorithm, or instead is structurally embedded and defined early in development following evolutionary pressures. To address this we record in the spinal cord of frogs using multielectrode probes and use information based clustering and conventional physiology to relate activity to modular primitives in the motor pattern. Our data support a number of dedicated distribution interneurons for organizing primitives. These impact the design and conceptualization of spinal prostheses.
Limits of Modularity Modularity in spinal cord may enable rapid organization of reflex responses and seed or bootstrap motor development. We examine the competence of modular mechanisms we identify using biomechanical models and simulation, and experimental testing. However, motor behavior in mammals also involves generation of novel motions of great sophistication and subtlety- in man novel motions never previously made by the species may be elaborated. We are consequently interested in how modularity in spinal organization figures in motor adaptation, corticospinal controls and more voluntary mechanisms. We have examined modularity in trunk as well as limb in the rat. Surprisingly, we found trunk control showed significantly less synergy modularity than leg muscle use. Individual muscles were the natural independent components in trunk motor patterns. This observation fits with a largely neglected but nonetheless significant mechanical role of trunk in adjusting quadruped locomotor patterns, and possibly with phylogenetically more ancient control mechanisms operating in axial muscles.

2. Modularity, adaptation, motor learning and BMI approaches after spinal injury in rats
The second line of investigation in our lab interweaves with the first. It is interesting and may be clinically relevant in the future to translate our understanding of modularity to recovery of function. We have begun to do this using thoracic spinal transections in adult and neonatal rats. The neonatal rats are especially interested because of the remarkable level of function some of them achieve.
Understanding the function that can be achieved by the injured neonatal injured rat About 20% of rats spinal transected on postnatal day 1 or 2 somehow succeed in developing a quadruped weight supported locomotion as adults, despite the complete separation of the lumbar spinal cord from the brain. The rats master the integration of actions generated by this autonomously operating piece of CNS into a coherent support behavior. This ability of the neonate may be a sign-post to mechanisms of recovery that might be engaged in adult injury in rats and translated to clinically relevant interventions.
Mechanical function and strategies of spinalized rats We have examined how neonatal injured rats with weight support as adults coordinate limb forces in stance and locomotion and how their motor cortex is organized. The integration of the autonomous hindlimbs involves containing and metering their activity in locomotion, and isolating them from perturbation in stance. In both these roles the trunk is crucially important.
Cortical organization and role of trunk controls in recovery in thoracic spinalized rats We used Intracranial Microstimulation (ICMS) of motor cortex and established all rats with weight supported locomotion after neonatal injury had mid to low trunk representation in motor cortex. ‘'Failed'’ rats did not. Lesion of the trunk region in weight supporting rats reduced quality of stepping measures by 40-50% and caused greatly increased pelvic roll. The cortex in these rats seems intimately engaged in locomotor control, significantly more than in intact rats. These results suggested that (1) the trunk could be a very important rehabilitation target, and that (2) cortical signals from trunk regions might be engaged in brain machine interface and neurorobotic strategies to improve locomotion. We are now exploring these ideas.
Brain Machine Interface designs We have developed a system that allows real-time BMI control of a robot for experiments in rats and frogs. We also developed an orthosis that can be implanted in the pelvis of rats. The robots we use can be attached to the orthosis to interact directly with the skeleton of the rat. In this way extrinsic (external world) or intrinsic (within body) force effects can be generated. Forces delivered in this way can be used for rehabilitative assistance following the control designs of the MIT-manus from the Hogan lab. They can be used to examine adaptation to altered external or internal mechanical conditions during locomotion. They can be used ‘'closed-loop'’ driven by recorded brain activity as a BMI. Preliminary experiments with this systems support the efficacy or this rehabilitation strategy, that robust adaptations with after effects can be examined, and that rats are capable of the rapid incorporation of BMI driven force effects into their adaptive strategies during locomotion.

Relevant Publications

Giszter SF, Kargo W, Shibayama M and Davies M.R. (1998) Fetal transplants placed into neonatal spinal transections in rats rescue axial muscle representations in adult motor cortex and improve recovery of l ocomotion. J Neurophysiol 80:3021-3030

Kargo WJ and Giszter SF. (2000), Rapid corrections of aimed movements by combination of force-field primitives. J Neurosci 20:409-426

Giszter SF, Grill W, Lemay M, Mushahwar V and Prochazka A. (2000) Intraspinal microstimulation: techniques, perspectives and prospects for FES, pp101-138 in Neural prostheses forrestoration of Sensory and motor function ed. KA Moxon and JK Chapin CRC Press

Hart CB and Giszter SF. (2004) Modular premotor drives and unit bursts as primitives for frog motor behaviors. J. Neuroscience 24(22):5269-82.

Murray M, Fischer I, Smeraski C, Tessler A, Giszter SF. (2004) Towards a definition of recovery of function. J Neurotrauma. 21(4):405-13.

Giszter SF, Hart CB. Udoekwere UI. Markin S, Barbe C. (2005) A Real-Time System for Small Animal Neurorobotics at Spinal or Cortical Levels. Neural Engineering. Conference Proceedings. 2nd International IEEE EMBS Conference March 16-19, 2005 Page(s):450 - 453

Udoekwere UI, Mbi LT, Ramakrishnan A, and Giszter SF. (2006) Robot applied elastic fields at the pelvis of the spinal transected rat: a tool for detailed assessment and rehabilitation. Proceedings of the IEEE/EMBC Conference, New York, NY.

Giszter SF, Davies MR Graziani VG (2007) Motor strategies used by rats spinalized at birth to maintain stance in response to imposed perturbations. J. Neurophysiol. 97(4):2663-75.

Giszter SF, Patil V and Hart CB (2007) Primitives, Premotor Drives and Pattern Generation: a combined Computational and Neuroethological Perspective. Prog. Brain Res. 165:325-349

Kargo WJ, Giszter SF. (2008) Individual premotor drive pulses, not time-varying synergies, are the units of adjustment for limb trajectories constructed in spinal-cord. J. Neuroscience. 28(10):2409-25

Giszter SF, Davies MR and Graziani V. (2008) Coordination strategies for limb forces during weight-bearing locomotion in normal rats, and in rats spinalized as neonates. Exp. Brain Research 190(1):53-69. Epub 2008 Jul 9.

Giszter SF, Davies MR, Ramakrishnan A, Udoekwere UI, Kargo WJ. (2008) Trunk sensorimotor cortex is essential for hindlimb weight-supported locomotion in adult rats spinalized as P1/P2 neonates. J. Neurophysiology 100(2):839-51. Epub 2008 May 28.

Silfies, SP, Bhattacharya A, Biely, S, Smith, S, Giszter, S. (2008) Trunk Control during Standing Reach: A Dynamical System Analysis of Movement Strategies in Patients with Mechanical Low Back Pain. Gait and Posture (Epub, and in press )

Reviews:
Giszter SF, Grill W, Lemay M, Mushahwar V, Prochazka A. (2000) Intraspinal microstimulation: techniques, perspectives and prospects for FES pp 101-138 in Neural prostheses for restoration of Sensory and motor function ed. KA Moxon and JK Chapin CRC Press

Giszter SF, Moxon KA, Rybak I, Chapin JK. (2000) A neurobiological perspective on design of humanoid robots and their components IEEE Intelligent Systems 15(4): 64-69

Giszter SF. (2003) Motor primitives Handbook of Brain Theory and Neural Networks (2nd ed) MIT Press.

Giszter SF. (2008) Spinal Cord Injury: Present and Future Therapeutic Devices and Prostheses. Neurotherapeutics 5(1):147-162.

Giszter SF. (2009) Motor Primitives. Encyclopedia of Neuroscience. (L.R. Squire, Editor). Oxford: Academic Press.


John Houle, Ph.D. –- Department of Neurobiology and Anatomy

Dr. Houle has a long standing interest in spinal cord injury and the potential to promote structural and functional repair in acute and chronic injury situations. It is important to understand that a spinal cord injury is an evolving condition where for weeks to months after injury there continues to be change/modulation of the cellular and molecular components affected directly or indirectly by the injury. These changes often are most prominent at the site of injury but it is critical that we also understand how cells/tissues remote to the injury are affected. An example would be the effect of spinal cord injury on neurons in the brain that normally transfer information through axon pathways that have been damaged. The response to injury by neurons in the brain may include cell atrophy, cell death, change in gene expression, retraction of the damaged axonal process or an attempt to re-grow the damaged axonal process.

Research in the laboratory is designed to examine multiple aspects of the neuronal and glial cell response to spinal cord injury with the intent of designing a combinatorial treatment strategy for regeneration leading to functional recovery. To accomplish this difficult task we use a variety of approaches, including: 1) neurotransplantation to provide a substratum that will support the regrowth of injured axons and which may provide a source of precursor cells to form new neurons and glial cells, replacing those lost after spinal cord injury; 2) treatment with neurotrophic and/or growth factors to provide essential molecules for cell survival and for initiating and maintaining axonal growth; 3) modulation of glial scar tissue and associated extracellular matrix to reduce the negative features of what has been characterized as a structural and chemical barrier to axonal growth; 4) exercise of injured limbs in the attempt to maintain joint fluidity and muscle strength and to re-train regions of the spinal cord that have been separated from descending input from the brain. There is strong evidence of activity dependent plasticity within the brain and spinal cord after exercise and we are especially interested in applying physical therapy and rehabilitation medicine techniques to determine if enhanced spinal cord plasticity will translate into greater behavioral recovery. As more information is gathered and placed into the puzzle, our understanding of the sequence of steps to be followed to promote recovery of function will become clearer.

Research techniques used in the laboratory range from gross anatomical examination to quantifying gene expression of single neurons. A typical experiment will include animal surgery, transplantation, physical therapy, a battery of behavioral analyses, preparation of tissue samples for light microscopy and immunocytochemical detection of specific cell types or tissue components, isolation of specific cells by laser micro dissection for extraction of RNA for analysis of gene expression by quantitative PCR, isolation of proteins for analysis of cell signaling by Western Blot or multiplex arrays.

Relevant Publications

Sandrow-Feinberg, H.R., J. Izzi, J. S. Shumsky, V. Zhukareva and J.D. Houle. Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury. J. Neurotrauma, In Press.

Sandrow, H.R., J. Shumsky, A. Amin and J. D. Houle. 2008. Aspiration of a cervical spinal contusion injury in preparation for delayed peripheral nerve grafting does not impair forelimb behavior or axon regeneration. Exp. Neurol. 210: 489-500.

Tom, V. and J.D. Houle. 2008. Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft. Exp. Neurol. 211: 315-319.

Dong, X., B. Keeler, W. Zhang, J. D. Houle and W.J. Gao. NMDA receptor subunit expression in GABAergic interneurons in prefrontal cortex: application of laser micro dissection technique. J. Neuroscience Methods, In Press.

Houle, J.D., V, Tom, D. Mayes, G. Wagoner, N. Phillips, J. Silver. 2006. Combining an autologous peripheral nerve bridge and matrix modification by chondroitinase allows robust functional regeneration across a hemisection lesion of the adult rat spinal cord. J. Neuroscience, 26: 7405-7415.

Beaumont, E., J.D. Houle, C.A. Peterson and P.F. Gardiner. 2004. Fetal spinal cord transplant and passive exercise help to restore motoneuronal properties after spinal cord transection in rats. Muscle & Nerve 29:234-242.

Dolbeare, D. and J.D. Houle. 2003. Glial cell line-derived neurotrophic factor (GDNF) promotes neuroprotection and neurorepair after spinal cord injury. J. Neurotrauma 20: 1251-1261.

Peterson, C.A., R.J.L. Murphy, E.E. Dupont-Versteegden and J.D. Houle. 2000. Cycling exercise and fetal spinal cord transplantation act synergistically on atrophied muscle following chronic spinal cord injury in rats. Neurorehab and Neural Repair 14: 85-91.

Dupont-Versteegden, E.E., R.J.L. Murphy, J.D. Houle, C.M. Gurley and C.A. Peterson 2000 Mechanisms contributing to restoration of muscle size with exercise and fetal transplants after spinal cord injury. Am. J. Physiol. 279: C1677-C1684.

Murphy, R.J.L., E.E. Dupont-Versteegden, C.A. Peterson and J.D. Houle. 1999 Two experimental strategies to restore muscle mass in adult rats following spinal cord injury. Neurorehab. Neural Repair 13:125-134.

 

Michel Lemay, Ph.D. –- Department of Neurobiology and Anatomy

My research interests are in movement control, and how neurophysiological findings may be applied to neuroprosthetics or orthotics design. Existing clinical neuroprostheses use electrical activation of the last-order neurons to individually command the muscles involved in producing movements. Thus, control of multi-joint motor behaviors remains one of the premier challenges for motor system neural prostheses. Since neurophysiology studies have shown the significant contribution of the spinal circuitry to movement control, the hypothesis is that electrical activation of spinal neural circuits, rather than direct activation of last-order motoneurons, will simplify generation of complex motor behaviors. Activation of these spinal circuits has been proposed as a possible new technique for the restoration of movement in spinalized individuals or the retraining/augmentation of regenerated pathways in the same population. My primary current project looks at the locomotor recovery provided by transplants producing nerve growth factors, combined with sensorimotor training of the locomotor circuitry, and the effects of these interventions on the motor output obtained by intraspinal microstimulation and the spinal interneurons activity.

Relevant Publications

H Barbeau, DA McCrea, MJ O'Donovan, S Rossignol, WM Grill, and MA Lemay. Tapping into spinal circuits to restore motor function. Brain Research Reviews, Vol. 30, pp. 27-51, 1999.

SF Giszter, WM Grill, MA Lemay, V Mushahwar, and A Prochazka. Intraspinal microstimulation: techniques, perspectives and prospects for FES.In Neural Prostheses for Restoration of Sensory and Motor Function. KA Moxon and JK Chapin, Eds., CRC Press, 2000.

MA Lemay, M Bhowmik-Stoker, GC McConnell and WM Grill. Role of biomechanics and muscle activation strategy in the production of endpoint force patterns in the cat hindlimb. The Journal of Biomechanics, Vol. 40, pp. 3679-3687, 2007.

VS Boyce, M Tumolo, I Fischer, M Murray and MA Lemay. Neurotrophic factors promote and enhance locomotor recovery in untrained spinalized cats” J Neurophysiology, Vol. 98, pp. 1988-96, 2007. Commentary by RD de Leon "Could neurotrophins replace treadmill training as locomotor therapy following spinal cord injury?" in same issue.

AS Burns, VS Boyce, A Tessler and MA Lemay. Fibrillation potentials following spinal cord injury: Improvement with neurotrophins and exercise. Muscle and Nerve, Vol. 35, pp. 607-613, 2007.

MA Lemay, D Grasse and WM Grill. Hindlimb endpoint forces predict movement direction evoked with intraspinal microstimulation in cats.” In press. IEEE Transactions on Neural Systems and Rehabilitation Engineering, 2009.

 

Gordon Lutz, Ph.D. –-Department of Pharmacology

The mission of our group is to develop drugs based on our innovative platform technology that combines small nucleic acid agents that modulate RNA splicing with functionalized nanocarriers. We are currently utilizing this platform technology to develop nanocarrier-oligonucleotide agents as safe and efficacious candidate drugs for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Our compounds under development for DMD and SMA consist of two components: (1) an antisense oligonucleotide (AO) which modulates pre-mRNA splicing of a target gene leading to expression of functional protein, and (2) nanocarrier molecules which facilitate the delivery of AOs to tissues including body musculature and heart (DMD) or spinal motor neurons and brain (SMA).

In our research we focus on a special class of chemically-modified AOs that bind to target pre-mRNA sequences and modulate RNA splicing with exceptional specificity and potency. AOs alone are not readily transported from the bloodstream to muscle or the CNS. Thus, a major emphasis of our laboratory is to develop novel nanocarriers that facilitate AO transport from the bloodstream to target cells (including transport across the blood-brain-barrier), and facilitate cellular uptake. This includes nanocarriers that provide cell-specific targeting and controlled (triggered) release of cargo.

Our group collaborates with numerous other faculty members from basic sciences and clinical departments across the Drexel campuses. Our research program benefits from the strong emphasis of Drexel University on nanotechnology, translational research, and drug discovery.

Relevant Publications
Glodde, M., Sirsi S.R., and G. J. Lutz. 2006. Physiochemical Properties of Low and High Molecular Weight PEG-Grafted Poly(ethylene imine) Copolymers and their Complexes with Oligonucleotides. Biomacromolecules. 7(1): 347-356.

Williams J. H., Sirsi, S. R., and G. J. Lutz. 2006. Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. Molecular Therapy. 14(1):88-96.

Sirsi, S. R., Schray, R. C., Williams J. H., Agisim M. E., and G. J. Lutz. 2008. Functionalized PEG-PEI copolymers complexed to exon skipping oligonucleotides improve dystrophin expression in mdx mice. Human Gene Therapy; 19(8):795-806.

Williams J. H., Sirsi, S. R., and G. J. Lutz. 2008. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice. BMC Biotechnology; 2;8:35.


Young-Jin Son, Ph.D. –- Department of Neurobiology and Anatomy

Our lab is interested in molecular and cellular basis of synapse plasticity in adult vertebrates. Neurons communicate each other through their specialized contacts called synapses, whose formation and maintenance are essential for proper functioning of the nervous system. Disturbance of such synapses in adults, therefore, by intrinsic or extrinsic factors such as pathological or physical damages, could be devastating. Notably, however, our nervous system has developed ways to cope with such occasions. Most prominently in the muscle, uninjured motoneurons sprout new axons and reestablish synaptic connections on injured muscle fibers, thus insuring muscle function and strength. In brain and spinal cord, limited but yet substantial plasticity of adult synapses has also been implicated in functional reorganization and restoration of adult brains. Our research goal is to elucidate biochemical mechanisms underlying such inherently extensive or limited plasticity of adult synapses. To this end, we currently focus on the role of perisynaptic glial cells (Schwann cells and astrocytes) as an active trigger of synapse plasticity both in muscle and spinal cord, a novel concept being developed in our laboratory. Various molecular and cellular techniques are being used, including state-of-the art tools and techniques such as in vivo imaging and transgenic mice. We hope that the work will lead to novel insights into synaptic roles of glial cells, pathogenesis of neurological and muscular diseases, and therapeutic strategy to repair synapses elsewhere in our nervous system.

Relevant publications

Megan Wright, Wha-Ja Cho, and Young-Jin Son. 2007. Ciliary neurotrophic factor elicits intrasynaptically trapped sprouting of motor nerve terminals released by Botulinum toxin-elicited topological sprouting: Implications for neuromuscular synapse repair. J. Comp. Neurol., in press *cover article.

Anthony S. Burns, Sabiha Jawaid, Hui Zhong, Hiroyuki Yoshihara, Srishti Bhagat, Marion Murray, Roland R. Roy, Alan Tessler and Young-Jin Son. 2007. Paralysis elicited by spinal cord injury evokes selective disassembly of neuromuscular synapses with and without terminal sprouting in ankle flexors of the adult rat. J. Comp. Neurol. 500:116-33.

Flora M. Love, Young-Jin Son and Wesley J. Thompson. 2003. Activity alters muscle reinnervation and terminal sprouting by inhibiting the formation of Schwann cell pathways linking synaptic sites. J. Neurobiol. 54:566-576.

Young-Jin Son, Todd W. Scranton, William J. Sunderland, Sung J. Baek, Jeffery H. Miner, Joshua R. Sanes and Steven S. Carlson. 2000. The synaptic vesicle protein SV2 is complexed with an a5-containing laminin on the nerve terminal surface J. Biol. Chem 275(1) : 451-60

Young-Jin Son, Joshua T. Trachtenberg and Wesley J. Thompson. 1996. Schwann cells induce and guide sprouting and reinnervation of neuromuscular junctions. Trends. Neurosci. 19(7): 280-285 *cover article.

Faculty Sponsors

Elizabeth Blankenhorn, Ph.D.
Department of Microbiology and Immunology
Drexel University
2900 Queen Lane
Philadelphia, PA 19129
215-991-8392
libby@drexelmed.edu

Jeffrey S. Deitch, Ph.D.
Assistant Professor
Department of Neurology
MS 423
Room 7126 New College Building
245 North 15th Street
Philadelphia, PA 19107
215-762-7693
jdeitch@drexelmed.edu

Simon Giszter, Ph.D.
Department of Neurobiology and Anatomy
Drexel University
2900 Queen Lane
Philadelphia, PA 19129
215-991-8412
(215) 843-9082 (fax)
simon.giszter@drexelmed.edu

Terry Heiman Patterson, MD
Professor of Neurology
Director MDA/ALS Center of Hope
Department of Neurology, MS 423
Room 7102 New College Building
245 North 15th Street
Philadelphia, PA 19107
215-762-7692
(215) 762-3161 (fax)
terry.heiman-patterson@drexelmed.edu

John Houle, Ph.D.
Department of Neurobiology and Anatomy
Drexel University College of Medicine
2900 Queen Lane
Philadelphia, PA 19129
(215) 991-8295
(215) 843-9082
jhoule@drexelmed.edu

Michel Lemay, Ph.D.
Department of Neurobiology and Anatomy
Drexel University
2900 Queen Lane
Philadelphia, PA 19129
215-991-8412
(215) 843-9082 (fax)
mlemay@drexelmed.edu

Gordon Lutz, Ph.D.
Department of Pharmacology
New College Building
245 N. 15th Street, MS#488
Philadelphia, PA 19102
215-762-2396
gordon.lutz@drexelmed.edu

Young Jin Son, Ph.D.
Department of Neurobiology and Anatomy
Drexel University
2900 Queen Lane
Philadelphia, PA 19129
215-991-8274
(215) 843-9082 (fax)
young-jin.son@drexelmed.edu

 

DREXEL UNIVERSITY COLLEGE OF MEDICINE

The Edward Jekkal Muscular Dystrophy Association Fellowship

Application Procedures

Purpose:
This program has been established to strengthen the training program for senior postdoctoral fellows about to move into faculty positions or junior research faculty members, including physician scientists, interested in neuromuscular disease research at Drexel University. The fellowship carries an annual award of $55,000 plus fringe benefits, with the possibility of a second year of funding.

Applicants are expected to identify a sponsor from within the training faculty at Drexel University and to prepare an application with the sponsor, who will provide the research support and, if appropriate, a salary supplement. Junior faculty at Drexel University can submit an independent application. The research project should be in an area consistent with the objectives of the Muscular Dystrophy Association.

One original and 6 copies of the completed application (with 2 letters of recommendation) should arrive at Drexel University by April 1, 2009. No late submissions or submissions sent by facsimile will be accepted.

Review Considerations:

Proposals will be judged by the Advisory Committee, with the aid of internal referees. The following criteria will be considered:

Review Criteria:
- Scientific and research background of the applicant
- Relevance of the proposed training to the career goals of the applicant
- Scientific quality of the proposal
- Appropriateness of the sponsor to the proposed training program and the sponsor’s commitment.

Specific Instructions for Applicant
Face Page
Self explanatory. If there will be multiple sponsors, list the primary one here.
The earliest possible start date for the fellowship is July 1, 2009.

Education Information
Applicant's Education - List all degree programs beginning with baccalaureate or other initial professional education. Include all dates (month and year) of degrees received or expected, in addition to other information requested.

Applicant's Training/Employment - List in chronological order all nondegree training, including postdoctoral research training, all employment after college, and military service. Clinicians should include information on internship, residency and specialty board certification (actual and anticipated with dates) in addition to other information requested.

Goals for Fellowship Training and Career - Explain training goals under this fellowship and the relevance to your career goals. Identify the skills, theories, conceptual approaches, etc. that you hope to learn or enhance your understanding of during the fellowship. Describe how the proposed activities, including any research, will contribute to the achievement of these career goals.

Abstract - State the broad, long-term objectives and specific aims of the research proposal, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Do not summarize past accomplishments and avoid the use of the first person. This is meant to serve as a succinct and accurate description of the proposed work when separated from the application.

Table of Contents
Self explanatory

Background
Support - Follow instructions on form.
Academic and Professional Honors - List any honors that would reflect upon your potential for a fellowship. Include current memberships in professional societies.
Title(s) of Thesis/Dissertation(s) - Self-explanatory.
Thesis Advisor or Chief of Service. If not submitting a reference from this person, explain why not.
Supplement - List plans, if any, developed with the sponsor to supplement the stipend.

Research
Summary - Summarize in chronological order your research experience, including the problems studied and conclusions. Specify which problems were theses. If you have no research experience, list other scientific experience. Do not list academic courses here. Do not exceed one page.
Doctoral Dissertation - Summarize, not exceeding one page.
Publications - In chronological order, list your entire bibliography, separating abstracts, book chapters, reviews, and research papers. For each publication, give the authors in published sequence, full title, journal, volume number, page numbers, and year of publication. Indicate if you have used another name previously. Manuscripts pending publication or in preparation should be included and identified.

Research Training Plan (Sections a-c) not to exceed 5 pages
Research Training Proposal - This section should be well formulated and presented in sufficient detail that it can be evaluated for both its research training potential and scientific merit. It is important that it be developed in collaboration with the sponsor. If multiple sponsors are envisioned, describe their individual roles.
a. Specific Aims - State the specific purposes of the research proposal and the hypothesis to be tested.
b. Background and Significance - Sketch briefly the background to the proposal. State concisely the importance of the research described in this application by relating the specific aims to broad, long-term objectives.
c. Research Design and Methods. Provide an outline of:
·Research design and the procedures to be used to accomplish the specific aims;
·Tentative sequence for the investigation
·Statistical procedures by which the data will be analyzed; and
·Any procedures, situations, or materials that may be hazardous to personnel and the precautions to be exercised.
Potential experimental difficulties should be discussed together with alternative approaches that could achieve the desired aims.
d. Literature Cited - Each citation must include names of all authors, titles, book or journal, volume number, page numbers, and year of publication.

Section II - Primary Sponsor

Facilities and Commitment
Follow instructions on form.

Checklist
The Checklist is the last page of the application.

Instructions for Submission of References
Applications will not be reviewed unless at least two references are received with the application. Applicants are responsible for complete applications reaching Drexel University on schedule.
Attach unopened references to the front of the original application and submit the entire package by the submission deadline.

Submitting Your Application
Submit the following materials in one package:

1. The original application, single sided, with signature. Note that the pages must be assembled in the order specified in the table of contents.
2. One original and 6 single-sided copies of the application. These should be made after signature.
3. At least 2 sealed letters of reference attached firmly to the Face Page of the original application.

Mailing Address
The Edward Jekkal Muscular Dystrophy Research Fellowship
c/o Dr. Itzhak Fischer
Department of Neurobiology and Anatomy
Drexel University
2900 Queen Lane
Philadelphia, PA 19129