Laura Balcer, MD, MSCE
Professor of Neurology at the Hospital of the University of Pennsylvania
Chief, Multiple Sclerosis Division, Department of Neurology

Dr. Balcer’s primary research focus is on the identification and development of clinical visual outcome measures for multiple sclerosis (MS) trials. Dr. Balcer’s group, funded jointly by the National Eye Institute and the National MS Society, focuses on determining which clinical tests best identify visual dysfunction in patients with MS. These studies have also examined the relation of visual function to neurologic impairment, magnetic resonance imaging abnormalities, and health-related quality of life. Data from these and other investigations at U. Penn have led to the inclusion of low-contrast letter acuity as a secondary outcome measure in 2 international MS treatment trials. A new ocular imaging technique, optical coherence tomography (OCT), has been used to examine retinal nerve fiber layer and macular thickness as biologic markers of neuronal and axonal loss in patients with MS.

Email: lbalcer@mail.med.upenn.edu
Phone: 215-349-8072

Gordon Baltuch, MD, PhD
Associate Professor, Dept. of Neurosurgery

Novel surgical strategies for the treatment of epilepsy and degenerative diseases. The biology of glia in disease.

Email: baltuch@mail.med.upenn.edu
Phone: 215-829-7144

Dr. Akiva Cohen
Assistant Professor, Department of Neurology

Our principal research interest is focused on the fundamental cellular and molecular mechanisms that underlie cognitive impairments associated with traumatic brain injury. We are primarily concerned with alterations in neuronal excitability in the limbic system of the brain. This system has been shown to play a primary role in higher cognitive function e.g. learning and memory and is damaged in traumatic brain injury. We incorporate a variety of techniques to understand the nature and functional consequences of injury-induced alterations.

Our studies begin with conditioned fear response behavior to assess cognitive impairments and extracellular recording to evaluate injured hippocampal function. Unbiased stereology is then used to quantify the degree of cell death. Excitatory and inhibitory synaptic recording is utilized to further determine the function of surviving neurons. Immunocytochemical and biochemical techniques are used to examine specific proteins that have been altered by injury and may be underlying synaptic and/or circuit dysfunction. The combination of these methodologies should help elucidate putative mechanisms causing injury-induced cognitive deficits. A better understanding of these injury-induced alterations will provide insight for directing the development of potential therapies that would ameliorate cognitive dysfunction in traumatic brain injured patients.

Email: cohena@email.chop.edu
Phone: 215-590-1472

Diego Contreras, MD, PhD
Associate Professor, Dept. of Neuroscience

My lab's focus is on how the intrinsic cellular properties of neurons and the characteristics of local neuronal networks contribute to the encoding of peripheral sensory input in two separate animal models: (i) the cat visual system and (ii) the rat whisker system. Responses to sensory stimuli are recorded from the neocortex and thalamus in vivo using intracellular and optical voltage-sensitive dye methods. These methods are also applied to the brain slice preparation in order to further study the dynamics of cortical microcircuitry. Using these techniques, we address a number of basic questions. Do differences in intrinsic cellular properties across individual neurons contribute to the representation of sensory inputs? How do local network properties such as feed-forward and feed-back inhibition shape the representation of peripheral stimuli? How do single cells acquire selectivity to specific stimulus features? How are thalamic and cortical receptive fields generated? How are responses to multiple sensory inputs integrated at different levels in the brain?

Email: diegoc@mail.med.upenn.edu
Phone: 215-573-8780

Douglas Coulter, PhD
Associate Professor
Department of Pediatrics, Division of Neurology

My research interests center on understanding the cellular and molecular mechanisms underlying the development of epilepsy. Symptomatic seizure disorders such as temporal lobe epilepsy are among the most prevalent and least medically responsive forms of epilepsy. They are also among the most interesting. A presumably normal individual receives some injurious stimuli, which, at some distant time point results in the initiation of an epileptic state, characterized by recurrent spontaneous seizures. A better understanding these seizure-initiating mechanisms should facilitate development of enhanced therapeutic strategies to improve treatment, and perhaps eventually contribute to the development of a cure for epilepsy.

My laboratory uses physiological, anatomical, and molecular techniques to address experimental issues relevant to epilepsy. Physiologically, my colleagues and I use patch clamp, intracellular, and extracellular recording techniques in both in vitro and in vivo preparations of animal or human brain. Anatomically, we use immunohistochemical and conventional staining techniques to characterize alterations occurring in the epileptic brain at a circuit level, including loss of populations of neurons, alterations in expression patterns of proteins, and axonal remodeling. Molecularly, we use a combination of semi-quantitative profiling of mRNA expression levels at the single cell level, in situ hybridization, retroviral transfection techniques, and antisense oligonucleotide knockdown of expression of certain proteins. The combination of these three diverse experimental approaches provides a powerful, synergistic approach to better understand critical factors contributing to the initiation of the epileptic condition.

Email: coulterd@email.chop.edu or coulterd@mail.med.upenn.edu
Phone: 215-590-1937

Peter Crino, MD, PhD
Associate Professor, Deptartment of Neurology

Research Focus: My laboratory is interested in understanding how aberrant development of the cerebral cortex contributes to pervasive neurological disorders such as epilepsy, mental retardation, and autism. Specifically, we are studying the molecular pathogenesis of cortical dyslamination in a variety of syndromes associated with these disorders including focal cortical dysplasia, heterotopias, tuberous sclerosis, and hemimegalencephaly. Our lab approach includes amplification of mRNA from single immunohistochemically labeled neurons in human brain specimens. We are able to determine the differential expression of numerous genes in a subset of phenotypically defined cells.

By quantifying the relative abundances of developmentally relevant genes, we hope to identify cellular pathways which, when disrupted, lead to abmormal layer formaton in the cerebral cortex. Finally, we study the cellular mechanisms that modulate proliferation of brain neoplasms such as primitive neuroectodermal tumors, gliomas, and subependymal giant cell astrocytomas in tuberous sclerosis.

Email: crinop@mail.med.upenn.edu
Phone: 215-898-0178

D. Kacy Cullen, PhD
Research Assistant Professor of Neurosurgery

Neurotrauma: conventional and blast-induced traumatic brain injury (TBI); neural cell/tissue biomechanics; injury tolerance criteria; mechanisms of acute neuronal failure and dysfunction; diffuse axonal injury; peripheral nerve injury; modeling traumatic neural injury in vitro and in vivo.

Neural Tissue Engineering: biomimetic 3-D neural constructs; neural cellular functionality in 3-D scaffolds; targeted nerve regeneration.

Biohybrid Neural Interface Microsystems: neural-prosthetic interfaces; biohybrid tissue engineered neural-electrical relays; 3-D in vitro neural interface microsystems.

Email: dkacy@mail.med.upenn.edu
Phone: 215-898-7945

Peter Davies, PhD
Professor of Pathology and Laboratory Medicine
Professor of Bioengineering
Director, Institute for Medicine and Engineering

Noted for driving vascular pathology in innovative and important directions, his work has consistently taken an integrative and highly interdisiplinary approach to endothelial mechanotransduction in cardiovascular physiology and pathology. As a graduate student he was the originator of endothelial functional change in early atherogenesis, and subsequently developed new directions for vascular cell communication, quantitative structure-function studies in living cells, and subcellular spatial mechanisms of endothelial mechanotransduction including a widely accepted model of decentralized signaling. Current research in his lab is directed at studies of multiscale ‘spatial’ genomics that defines endothelial phenotypes as a function of regions of susceptibility to, or protection from, atherosclerosis (arteries) and calcification (heart valves). He is the author of >150 peer reviewed papers in cardiovascular, biomedical engineering, and basic science journals, and has trained more than 40 students and postdoctoral Fellows.

Email: pfd@pobox.upenn.edu
Phone: 215-573-6813

John Detre, MD
Associate Professor of Neurology & Radiology

Overall research focuses on cerebral blood flow and metabolism under normal and conditions and in response to brain injury. Specific conditions under investigation include functional activation of human brain in response to cognitive and sensorimotor tasks, epilepsy, cerebrovascular disease, and strokes. This research primarily utilizes magnetic resonance techniques including functional imaging techniques and spectroscopy, often correlated with other methods. There is a large component of data analysis and processing using statistical parametric mapping and other computational methods. In addition, the physiological basis and pathophysiological influences on functional activation are studied using a rat model. The research is carried out in collaboration with investigators from Radiology Research, the Cerebrovascular Research Center, Cognitive Neurology, and the Epilepsy Center.

Email: detre@mail.med.upenn.edu
Phone: 215-349-8465

Marc Dichter, MD, PhD
Professor, Department of Neurology

Research focuses on basic mechanisms of epilepsy, mechanisms underlying the development of seizures and one's ability to predict seizure onset, mechanisms by which brain stimulation can suppress seizure development and spread, the physiology and pharmacology of synaptic transmission between hippocampal neurons, the developmental cell biology of cortical and hippocampal neurons maintained in cell culture, and characteristics of pleuripotent neural progenitor cells. Ongoing projects focus on chronic recording from awake, behaving epileptic animals in order to characterize their seizures, develop methods to predict seizure onset well before it occurs and develop methods to stimulate the brain in order to prevent ictogenesis. The long-range goal is to develop an implantable closed loop feedback device to predict and prevent seizures. Other projects in the lab, have included an analysis of the differential effects of frequency dependent processes on inhibitory and excitatory synaptic transmission in cultured hippocampal neurons, the regulation of GABA mediated synaptic transmission, the regulation of excitatory neurotransmitter action, the molecular regulation of receptor choice and neurotransmitter phenotype, and mechanisms of progenitor cell differentiation into neurons.

Email: dichter@mail.med.upenn.edu
Phone: 215-349-5166, Lab: 215-898-3130

James Eberwine, PhD
Professor, Dept. of Pharmacology

The research efforts of my laboratory are directed towards understanding the molecular basis of neuronal functioning. Our experimental approach is reductionist in nature and involves analysis of gene expression in individual cells dispersed in culture, in the live slice preparation or from fixed pathological tissue specimens. We have developed various procedures that have enabled the analysis of cellular functioning using single cells as the experimental model. These procedures include those that permit an analysis of the mRNA complement, the protein complement and an assessment of mRNA movement and translation within single cells. This level of analysis is important since an individual cells biochemical compostion may be diluted by that of surrounding cells. We are currently generating molecular and bioprocess fingerprints of various cell types and disease states. When this is complete, we hope that it will be possible to alter the cellular response to various challenges by altering the levels of these biological processes in a predictable manner. As part of these studies, we are examining the role of subcellular localization of mRNAs in regulating cellular function. We have shown that multiple mRNAs are localized in neuronal dendrites and have provided a formal proof of local mRNA translation in dendrites. Further, we have recently shown that the intracellular sites of localization and translation of these mRNAs can be altered by synaptic stimulation highlighting for the first time that in vivo translation of a mRNA can occur at different rates in distinct regions of a single cell (translation is primarily exponential in dendrites and linear in the cell soma). These insights into the cell biology of neuronal function highlight the complexities that remain to be understood.

Email: eberwine@pharm.med.upenn.edu
Phone: 215-898-0420

Sean Grady, MD
Chairman & Charles Harrison Frazier Professor of Neurosurgery
Dept. of Neurosurgery

Research interests include memory dysfunction resulting from traumatic brain injury and minimally invasive neurosurgery. His clinical focus is in the area of Cranial Base Tumors, Pituitary Tumors, Meningiomas, Schwannomas, Malignant Skull Base Tumors as well as Cerebrovascular Disorders, Aneurysms, AVM's. Dr. Grady and Dr Bert O’Malley (Chairman, Department of Otorhinolaryngology, Head and Neck Surgery) are co-directors of the Cranial Base Center. In addition, he performs general neurosurgery procedures for herniated discs of the back and neck.

Email: gradys@uphs.upenn.edu
Phone: 215-349-8325

Joel Greenberg, PhD
Research Professor, Dept. of Neurology

Stroke: A crucial factor determining the prognosis of patients in cerebral ischemia is the ability of tissue to recover from biochemical and hemodynamic derangements. We are investigating the factors that contribute to irreversibility of tissue damage in focal cerebral ischemia. Studies are being conducted in cats and rats in which the middle cerebral artery is temporarily occluded. Parameters that are measured include local cerebral glucose metabolism, local cerebral blood flow, tissue metabolites (high energy phosphates) and, tissue nitric oxide concentrations. These parameters are correlated with regional histological damage.

Activity dependent plasticity studies are being undertaken in the rat to examine the effect of somatosensory deafferentation on the relationship between local cerebral blood flow and local cerebral glucose metabolism. Double label autoradiography is being used.

Studies are currently in progress to examine reorganization of the blood flow, metabolic, and functional response following focal cerebral ischemia of the somatosensory cortex of the rat. A novel compression ischemia model has been developed to facilitate these studies.

Email: joel@mail.med.upenn.edu
Phone: 215-662-6351

James G. Hecker, MD, PhD
Assistant Professor of Anesthesiology & Critical Care

Non-viral gene delivery, transient gene expression, cationic lipid medicated gene delivery, delivery to brain/CNS, delivery to spinal cord, neuroprotection, preoperative, heat shock proteins, stroke, traumatic brain injury, traumatic spinal cord injury, molecular biology, neurosciences, cloning

Email: heckerj@uphs.upenn.edu
Phone: 215-349-5343

Mark Helfaer, MD
Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia;
Senior Anesthesiologist and Attending Physician

Dr. Mark Helfaer's interests include the effects of anesthesia on patients with obstructive sleep apnea and the care of bran injured children; intensive care; cerebral pathophysiology and the role of nitric oxide in the normal control of the cerebral vascular system.

Email: HELFAER@email.chop.edu
Phone: 215-590-5505

Jimmy W. Huh, MD
Associate Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia;
Attending Physician, Pediatric Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine

Pediatric Traumatic Brain Injury

Email: huh@email.chop.edu
Phone: 215-590-5505

Michael Kahana, PhD
Professor, Dept of Psychology
Director, Computational Memory Lab

I am interested in human episodic memory for verbal, visual and spatial information. To study this general problem, I conduct experiments that measure behavioral and electrophysiological responses during memory tasks, and develop computational models to explain the resulting data. Our lab is one of several in the world studying the electrophysiological responses of neurons through direct intracranial electroencephalographic (iEEG) recording from the living human brain. Such recordings can be obtained from epilepsy patients who have had electrodes surgically implanted on the cortical surface of the brain or through the medial temporal lobes (including hippocampus) as part of the clinical process of localizing seizure foci. By analyzing how brain activity, including the responses of individual neurons, correlates with task variables, we are able to study the neurophysiological basis of memory with a high degree of spatial and temporal resolution. Current projects include studies of spatial navigation using a virtual taxi driver game, and computational modeling of the role of temporal context in visual and verbal memory.

Email: kahana@sas.upenn.edu
Phone: 215-746-3501

John Y.K. Lee, MD
Assistant Professor of Neurosurgery

Dr. Lee has a passion for minimally invasive ways to treat brain and spine tumors. This passion is expressed as a commitment to endoscopic approaches through the nasopharynx or oropharynx to remove pituitary, clival, and skull-base tumors. Another expression of his interest in minimally invasive methods is his devotion to stereotactic radiosurgery, eg. "incision-less" brain surgery.

In addition to brain tumors, Dr. Lee is committed to the comprehensive treatment of patients with craniofacial neuralgias, including trigeminal neuralgia, glossopharyngeal neuralgia, and hemifacial spasm. Dr. Lee uses minimally invasive surgical procedures including microvascular decompression (Jannetta procedure) and stereotactic radiosurgery to cure these disorders.

Email: leejohn@uphs.upenn.edu
Phone: 215-829-7144

Virginia M-Y Lee, PhD, MBA
The John H. Ware 3rd Professor in Alzheimer's Research,
Dept. of Pathology and Lab Medicine

Virginia M.-Y. Lee’s research interest focuses on tau, alpha-synuclein and amyloid beta precursor protein (APP), and their roles in the pathobiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), and frontotemporal dementias (FTD). In particular, Dr. Lee wants to determine the pathogenesis of senile plaques, Lewy bodies and neurofibrillary tangles because these are major lesions found in the brains of AD patients and other neurodegenerative diseases. Information obtained from this research program may shed light on how neurons degenerate in AD and PD and lead to a better understanding of the etiology of these diseases. A multi-disciplinary approach (including biochemical and molecular studies of neuronal culture systems, animal models and human tissues obtained at autopsy) is used in the laboratory to address these research issues in common with these neurodegenerative diseases. Other research efforts focus on an increased understanding of the normal functions of tau, synuclein, and APP. Dr. Lee is involved in collaborative initiatives to advance drug discovery in Alzheimer’s disease and Parkinson’s disease.

Email: vmylee@mail.med.upenn.edu
Phone: 215-662-6427

Peter LeRoux, MD, FACS
Associate Professor, Dept. of Neurosurgery

A fundamental event in neuronal differentiation and subsequent function of the nervous system is the development of axons and dendrites. My laboratory investigates how neurons grow and maintain these two distinct types of processes. In addition we are investigating how these processes may recover or regenerate after an injury. The studies are performed in dissociated cultures of the mammalian cerebral cortex and using an organotypic culture system that allows us to investigate axonal regeneration in the mature nervous system and the effects of deafferentation on dendritic morphology. Specific areas of investigation include the influence of different types of astrocytes or stem cells, the role of excitatory amino acids, the effects of trophic factors such as the BMPs, the Rho family of GTPases, signal transduction pathways particularly Smad proteins, and proteins such as Notch or noggin that regulate cell fate decisions during early development. In addition to evaluating these various cellular and molecular mechanisms during normal development, they are also evaluated using in vitro models of head injury and ischemia. Recently we have begun translational research to examine BMP release in models of - and in patients with head injury.

Email: peter.leroux@uphs.upenn.edu
Phone: 215-829-7072

Susan Margulies, PhD
Professor of Bioengineering and Neurosurgery

Cells within the body routinely tolerate deformations during activities such as head turning and breathing, yet when cells are deformed beyond a safe limit or injury threshold, function and structure are altered temporarily or even permanently. Our goal is to determine functional and structural injury thresholds in the brain and lung, and use them to understand mechanisms of traumatic brain and lung injury. In addition, our study of the biochemical and molecular biology of injured cells facilitates the development of preventive and therapeutic measures.

Because human tissues tend to be inhomogeneous, anisotropic and nonlinear, and the tissues of interest undergo large strains, determining the complex relationship between cellular and macroscopic responses requires an integrated biomechanics approach consisting of several simultaneous rigorous engineering experimental and theoretical analyses. Tissue mechanical properties and injury thresholds are measured and used to develop computational models. These models are used to generalize our experimental cell and tissue findings and determine macroscopic injury mechanisms.

Applications of current work are in the areas of traumatic head injury in adults and children, and ventilator-induced lung injury. These studies parallel clinical investigations regarding the treatment and detection of traumatic injury.

Email: margulie@seas.upenn.edu
Phone: 215-898-0882

David Meaney, PhD
Professor and Chair of Bioengineering

The process of mechanotransduction is critical in understanding the response of cells and tissues of the central nervous system (CNS) to traumatic injury. In this research area, experimental work is combined with mathematical modeling to provide a method to quantify the effect of physical forces on cell and tissue function. For example, some of the research combines finite element models of the brain with experimental work to estimate the tissue mechanical stress/strain associated with biological markers of injury. These models provide a starting point to relate traditional measures of stress to the microstructural constituents of the tissue. Structural models are being developed to link global mechanical deformations and the resulting deformation of cellular/subcellular microstructures in the CNS white matter. With the kinematic transformations between the macroscopic deformations and cellular components of the CNS white matter now better established, the research has expanded to determine the mechanism(s) by which a mechanical signal is converted into a biochemical signaling cascade for organotypic tissue, cultured neurons, and cultured axons.

Email: dmeaney@seas.upenn.edu
Phone: 215-898-8501

Robert Neumar, MD, PhD
Associate Professor of Emergency Medicine

Brain ischemia caused by cardiac arrest and stroke kills 300,000 people and disables another 150,000 each year in the United States. Other than early reperfusion, we have no clinically proven therapy to reduce post-ischemic brain damage. After an ischemic insult, neuronal death is delayed for hours to days. This interval represents a potential therapeutic window. The general goal of my research effort is to characterize the molecular events that cause delayed neuronal death after brain ischemia and develop clinically effective therapies to minimize brain damage after cardiac arrest and stroke.

The current research in my lab is focused on the molecular mechanisms of delayed neuronal death in post-ischemic neurons. Brain ischemia causes immediate intracellular Ca2+ overload that resolves within 1-2 hours of reperfusion. Subsequently, a secondary delayed disruption of Ca2+ homeostasis is observed which is temporally associated with the onset of delayed neuronal death. The mechanism of this secondary disruption of Ca2+ homeostasis remains unclear and potentially involves dysfunction of Ca2+ regulatory proteins in the plasma membrane, endoplasmic reticulum and mitochondria. Our experimental approach to this question involves functional analysis of Ca2+ regulatory proteins in post-ischemic neurons coupled with direct measurement of subcellular Ca2+ concentrations using x-ray diffraction microanalysis.

A second line of investigation involves analysis of proteolytic cascades in the post-ischemic neurons. Both calpain and caspase proteolytic pathways are activated in the brain after ischemia and reperfusion. While early investigations have linked caspases to apoptosis and calpains to necrosis, there is a growing body of evidence that signficant cross-talk occurs between these two pathways. Our work is focused on determining the causal role these and other proteolytic pathways play in delayed post-ischemic neuronal death. We have recently characterized the time course and location of both calpain and caspase activity in our model of transient global brain ischemia. Our current experimental approach involves biochemical and molecular manipulation of these proteolytic cascades.

Email: neumarr@uphs.upenn.edu
Phone: 215-898-4960

Donald O'Rourke, MD
Associate Professor of Neurosurgery

Dr. O'Rourke is interested in the cell and molecular biology of erbB family receptor tyrosine kinases, including the ErbB1/Epidermal Growth Factor Receptor (EGFR) and the p185ErbB2/neu receptor kinases.

In addition to studying the mechanisms of cell growth and transformation induced by EGFR family proteins, Dr. O'Rourke has developed receptor-based strategies which facilitate apoptotic cell death in EGFR-containing glioblastoma cells.

Dr. O'Rourke's present research aims can be summarized as follows:

• To understand the mechanisms of cell death in erbB receptor-containing glial cells during normal development and following oncogenic transformation.
• To understand the biochemical mechanisms of erbB signal attenuation in transformed glial cells of the central nervous system.
• To apply this understanding to the design of rational, biologically-based drugs fordiseases such as malignant glioma and CNS neurodegenerative pathologies.

Email: donald.orourke@uphs.upenn.edu
Phone: 215-662-3490

Randall Pittman, PhD
Professor, Dept. of Pharmacology

Cellular and molecular approaches are used to study the normal and pathological functions of the polyglutamine neurodegenerative disease protein, ataxin-3, and signaling pathways controlling the execution stage of apoptosis. Apoptosis experiments focus on understanding regulation of execution events by Rho kinase signaling pathways with particular emphasis on dynamic membrane blebbing, cell fragmentation, and cellular processes that prepare cells for phagocytosis. Studies on the polyglutamine disease protein, ataxin-3, focus on understanding its normal cellular functions as a deubiquitylating enzyme and how this may be related to its pathology in spinocerebellar ataxia type 3/ Machado-Joseph disease. Ongoing projects are investigating the role of ataxin-3 in the ubiquitin proteasome pathway, interaction with DNA repair proteins, and neuronal transport mechanisms. Ataxin-3 is the first member of a new family of deubiquitylating enzymes and we are currently characterizing cellular and biochemical properties of other members of this new family of enzymes.

Email: pittman@pharm.med.upenn.edu
Phone: 215-898-9736; Lab: 215-898-7099

James Schuster, MD, PhD
Assistant Professor of Neurosurgery at the Hospital of the University of Pennsylvania

Dr. Schuster is interested in the basic mechanisms of prostate cancer metastasis to the spine. Prostate cancer has a very strong predilection for spread to bone with the spine being a major area of metastatic involvement. Spinal cord compression is the first sign of prostate cancer in an estimated 12-19% of patients, and loss of ambulatory function significantly shortens life expectancy. In addition to neurologic compromise, spinal involvement and pathologic fractures are a major source of lifestyle limiting pain and suffering. Current therapies including radiation, surgery, and androgen ablation generally only provide temporary relief. We are interested in the role of growth factors such as IGF-1 in tumor proliferation in bone and are working to develop specific local therapy for metastatic disease.

Email: schustej@uphs.upenn.edu
Phone: 215-615-1624

Robert Siman, PhD
Research Associate Professor of Neurosurgery

Recent advances in cell biology and genetics have led to an explosion of information about intracellular signaling mechanisms for nerve cell death, and the identification of gene mutations responsible for inherited forms of many neurodegenerative diseases. There are, however, several challenges for converting these advances in basic neurobiology to new and effective treatments. Toward meeting these challenges, my laboratory is identifying specific cell death signaling pathways that underlie particular neurodegenerative processes in the brain, defining pathogenic mechanisms by which disease-causing mutations impact these signaling pathways, and devising non-invasive surrogate markers for detecting distinct modes of neurodegeneration in the brains of living organisms.

Our signaling work focuses on brain proteases, now recognized as critical mediators of both apoptotic and necrotic modes of neuronal death, as well as the abnormal protein aggregation that is a pathological hallmark of Alzheimer’s and other neurodegenerative disorders. The laboratory developed an antibody-based technology known as protease fingerprinting for measuring activation of specific proteases, localizing their activation at the anatomical level, and identifying their protein substrates that are potential downstream effectors of cell death signaling. Protease fingerprinting has also led to the identification of surrogate markers that are measurable in cerebrospinal fluid and serum following brain injury in both experimental animals and human patients, and indicate the magnitude of the brain damage, the underlying signaling mechanisms involved, and the efficacy of candidate neuroprotective treatment regimens. By developing a panel of such markers for neurodegeneration along with immunoassays for their highly sensitive and specific quantitation, we aim to impact the diagnosis, prognosis, and treatment of acute brain injuries in numerous clinical settings.

Another focus has been the characterization of a faithful mouse genetic model of Alzheimer’s disease (AD), developed by “knocking in” disease-causing mutations in amyloid precursor protein and presenilin-1 into their endogenous mouse genes. We are using this disease model to understand how an imbalance in protease activities leads to abnormal protein accumulation, discern how protein aggregates impact forms of adaptive plasticity in neural pathways that are both critical for long-term memory and severely impacted in AD, and identify treatment strategies for reducing the pathology and restoring the neural plasticities.

Email: siman@mail.med.upenn.edu
Phone: 215-898-9161

Douglas H. Smith, MD
Professor of Neurosurgery
Director of the Center for Brain Injury & Repair

Current research interests include the mechanics of diffuse axonal injury, magnetic resonance techniques for diagnosis of axonal injury, cognitive dysfunction due to traumatic brain injury, and the link between neurodegenerative diseases and brain trauma.

In addition, his laboratory creates nerve constructs to repair the damaged spinal cord and peripheral nerves. These efforts have resulted in over 100 published reports.

Email: smithdou@mail.med.upenn.edu
Phone: 215-573-3156

John Q. Trojanowski, MD, PhD
William Maul Measey-Truman G. Schnabel, Jr. MD Professor of Geriatric Medicine and Gerontology
Department of Pathology and Laboratory Medicine

Research currently centers on molecular mechanisms of neuron dysfunction, degeneration and death in normal aging and in neurodegenerative diseases (Alzheimer's and Parkinson's disease, frontotemporal dementias with/without parkinsonism, motor neuron disease, etc.). This research uses immunological, biochemical, genetic, molecular and morphological methods to study human CNS and PNS tissue samples (postmortem or surgical), cell lines, synthetic proteins, and transgenic models of neurodegenerative diseases. Dr. Trojanowski is involved in collaborative initiatives between PENN Medicine and the University of Pennsylvania School of Nursing to advance drug discovery, clinical research, and patient care related to Alzheimer's disease and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease.

Email: trojanow@mail.med.upenn.edu
Phone: 215-662-6399

Deborah Watson, PhD
Research Assistant Professor of Neurosurgery

Research interests include: (1) Viral vector-mediated, targeted gene delivery to the CNS; (2) Use of viral vectors and neural stem cells to deliver trophic factors in the injured CNS; (3) MRI monitoring of migration of transplanted neural stem cells in the mouse CNS; (4) Mechanisms of migration of neural stem cells towards areas of CNS pathology.

Email: djw3@mail.med.upenn.edu
Phone: 215-662-7931

William Welch, MD, FACS, FICS
Professor of Neurosurgery
Chief of Neurosurgery, Pennsylvania Hospital
Research Assistant Professor of Neurosurgery

Research Focus: Dr. Welch is the Co-Director of the Neurosurgical Biomechanical Research Laboratory and oversees research related primarily to biomechanical assessments of the treated and untreated spine. His clinical activities and clinical trials revolve around spinal disorders and motion preservation.

Email: william.welch@uphs.upenn.edu
Phone: 215-829-6700

Frank Welsh, PhD
Professor of Biochemistry in Neurosurgery

The brain is extremely vulnerable to ischemia. Loss of blood flow for only a few minutes triggers pathologic cascades that culminate in the death of the most vulnerable neurons. However, recent studies have demonstrated that this vulnerability can be dramatically reduced by preconditioning the brain with brief ischemia or cortical spreading depression. These results indicate that there are intrinsic mechanisms that protect neurons against ischemia. The objective of the lab is to identify those mechanisms and to explore therapeutic modalities based on them. In addition, the lab is developing RNA vectors to overexpress selected proteins in the brain.

Email: fwelsh@mail.med.upenn.edu
Phone: 215-662-7925

Beth Winkelstein, PhD
Associate Professor of Bioengineering

The current understanding of painful neck injury mechanisms remains quite limited, drawing largely on clinical and epidemiological speculations. The broad goal of the work in our laboratory is to understand the mechanisms of injury that produce whiplash, sports-related, and other painful injuries. By combining biomechanical and immunological techniques we can define the relationships between injury to the cervical spine/neck and physiological cascades of persistent pain. Particular emphasis is placed on understanding injury to individual structures in the neck, such as the facet joints, nerve roots and spinal cord and how mechanical loading to these structures elicits pain. Through this work we can begin to develop thresholds for mechanical injury that produce persistent pain; and work towards a definition of the neck's tolerance for painful injury.

Additional research efforts are aimed at understanding the role of biomechanics in the neuroimmunologic changes of the central nervous system that contribute to persistent pain. Understanding neck pain mechanisms requires merging both biomechanics and neuroimmunology. As such, work in our laboratory integrates experimental and theoretical approaches in an effort to understand biomechanics of pain. This requires integrated research at both the cellular and macroscopic tissue levels and efforts are focused on describing the mechanical and physiological responses at both of these levels.

Applications of current work are in the areas of automotive and whiplash-related injury and sports injuries. Studies in our laboratory complement other related clinical studies investigating neck pain and have implications for design efforts in automobiles that are aimed at preventing whiplash injuries. Future efforts will also help determine the most effective pharmacological treatments and clinical management strategies for neck pain.

Email: winkelst@seas.upenn.edu
Phone: 215-746-0132

John H. Wolfe, VMD, PhD
Professor, Pathology and Medical Genetics, School of Veterinary Medicine
and Department of Pediatrics, School of Medicine
Director, Walter Flato Goodman Ctr for Comparative Medical Genetics

My research focuses on somatic cell gene transfer to the brain. Animal homologues of human neurodegenerative genetic diseases are used as test systems for gene transfer by viral and other vectors. The primary model system is mucopolysaccharidosis (MPS) type VII (Sly disease), a lysosomal storage disorder caused by a deficiency of ß-glucuronidase, which blocks the normal cellular breakdown of glycosaminoglycans. MPS VII animal models (mice, dogs, and cats) are excellent experimental systems to study the fate of gene transfer and cell transplantation in the brain because both the transferred ß-glucuronidase enzymatic activity and changes in pathology can be studied. Several approaches are being investigated and compared to develop technologies that can tailored to specific applications. These are expected to be especially useful in genetically manipulating discrete populations of cells within the developed brain. Ex vivo gene transfer is being studied using retrovirus vector-corrected cells which are transplanted directly into the brain to circumvent the blood-brain barrier. Fibroblasts grafts are used to evaluate variations in vector designs for their ability to support sustained expression of the transferred gene. Multipotent neural progenitor cells, which differentiate into mature normal cells appropriate to their location within the brain, are being evaluated for their ability to deliver engineered cells to many regions of the diseased brain. Direct transduction of brain cells is being evaluated with herpesvirus, adeno-associated virus, and lentivirus vectors. The methods are being evaluated in post-natal and fetal animals.

Email: jhwolfe@vet.upenn.edu.
Phone: 215-590-7028