Dr. Amy Brooks-Kayal

Current work focuses primarily on changes in GABA(A) receptors, which mediate the majority of fast synaptic inhibition in brain. GABA(A) receptors are composed of multiple receptor subunits, and different subunits confer distinct functional and pharmacological properties to the receptor.

Other areas of research in our laboratory focus on how treatment with antiepileptic drugs which act at the GABA(A) receptor, such as phenobarbital and benzodiazepines, may impact on receptor development, and on the use of gene therapy to re-constitute normal GABA(A) receptor subunit expression following status epilepticus to prevent subsequent development of spontaneous seizures.

Email: kayal@email.chop.edu
Phone: 215-590-2241

Dr. Akiva Cohen

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.

Email: cohena@email.chop.edu

Dr. Douglas Coulter

My research interests center on understanding the cellular and molecular mechanisms underlying the development of 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.

Dr. Peter Davies

Research interests are focused upon molecular mechanisms of cardiovascular diseases, particularly arterial biology and pathology (atherosclerosis). Of major research interest are the mechanisms of interaction of hemodynamic forces with the vascular endothelium and vascular cell-cell interactions. Experimental approaches range from cell and molecular biology, membrane biophysics, to biomechanics and computational fluid dynamics.

Dr. Marc Dichter

Dr. Dichter is actively involved in several research areas of neuroscience. For a number of years he has been analyzing mechanisms by which seizures develop in the brain. He has focused on studying short term, frequency-dependent plasticity between hippocampal excitatory and inhibitory neurons, both in dissociated cell culture and in cultured hippocampal slices.

His work focuses on both presynaptic and postsynaptic changes in synaptic function and involves patch clamp recordings from pairs of synaptically coupled neurons. In addition, the research examines pharmacological modulation of excitatory and inhibitory synaptic receptors and the correlation of receptor subtype with physiological actions. He has also been analyzing the molecular differences between excitatory neurons and inhibitory neurons in mammalian CNS, using single cell mRNA expression profiling in collaboration with Dr. Jim Eberwine.

Dr. Dichter is also involved in a number of clinical studies in epilepsy, including the investigations of new antiepileptic drugs, the use of deep brain stimulation to suppress seizures, and methods for preventing epileptogenesis after head injury and other "insults" to the brain.

Dr. James Eberwine

Dr. Eberwine's laboratory studies the molecular mechanisms of cellular plasticity. Critical to these studies has been the development of several technologies which permit analysis of gene expression in small amounts of tissue including single cells.

Areas of active investigation include studying of age, glucocorticoid and opiate induced changes in the expression profile of identified neurons. These studies have been expanded to include an analysis of the subcellular distribution of mRNAs in developing and mature neurons.

Additional emphasis has been placed on studying the role of RNA binding proteins in regulating gene expression with the following model systems under investigation - the stress response of the HPA-axis, the role of FRA-X and family members in controlling signal transduction in synapses and the interaction of proteins with the CAG-repeats present in Huntingtin mRNA.

Dr. Sean Grady

Dr. Grady's current bench research focuses on the consequences of traumatic brain injury on the hippocampus. Using mice and the fluid percussion injury model,he is exploring the mechanisms within the hippocampus that underlie cognitive recovery after brain injury using anatomic, electrophysiologic, and molecular techniques. In particular, the work focuses on the role that the contralateral hippocampus plays in functional recovery. Techniques include determination of neuronal survival using design based stereology, analysis of dendrite morphology by selectively filling specific neurons with fluorescent dyes and exploiting specific genetic manipulations within mice to analyze specific inhibitory neuronal populations. The physiologic consequences of injury are analyzed using in vitro hippocampal slice recordings, both field and single cell recording. Finally, the functional outcome is assessed using the hippocampal dependent conditioned fear paradigm.

Email: sean.grady@uphs.upenn.edu

Dr. Joel Greenberg

Dr. Greenberg's current projects are Activation in Stroke -Implications for Rehabilitation, The Role of Nitric Oxide in Cerebral Ischemia, Physiology and Pathophysiology of Activation Flow Coupling, and Flow in ThickTissues Probed by Diffusing Light.

Email: joel@mail.med.upenn.edu

Dr. Mark Helfaer

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

Dr. Virginia Lee

Major research interest focuses on the neuronal cytoskeleton, synucleins and amyloid beta precursor proteins, and their roles in the pathobiology of neurodegenerative diseases such as Alzheimer's disease (AD). In particular, we wish to determine the pathogenesis of senile plaques (a lesion in which altered neuronal cytoskeletal proteins consistently associated with extracellular deposits of amyloid fibrils), Lewy bodies and neurofibrillary tangles because these are major lesions found in the brains of AD patients and other neurodegenerative diseases.

Information obtained from research program may elucidate how neurons degenerate in AD and lead to a better understanding of the etiology of AD. 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 AD.

Basic information obtained here is being utilized to increase our understanding of the function of the normal neuronal cytoskeleton and the role of the neuronal cytoskeleton in neurodegenerative diseases such as AD.

Dr. Susan Margulies

Traumatic brain injury is the most common cause of death in childhood, and injury in infancy results in higher morbidity and mortality than that seen in older children. Traditionally, the medical and engineering communities have assumed that children respond as miniature adults. However, using animal experiments, human and animal tissue tests, clinical studies, anthropomorphic surrogate tests, and computational simulations we have determined that thresholds and mechanisms associated with severe brain injury vary with the age of the child, because the mechanical properties of the tissues, their response to deformation and the size of the structures change during development.

Specifically we have developed the only immature animal model that recreates the graded diffuse white matter injuries seen in children, ranging from brief concussion to prolonged periods of unconsciousness. We use this model to correlate rapid head accelerations with histopathological and functional (behavior, cognition, motor) responses in mild, severe, and even repeated head injuries

We have published over a dozen papers reporting detailed measurements of the mechanical properties of brain tissue – together this body of literature defines the nonlinear, anisotropic viscoelastic, age-dependent, and species-dependent aspects of living and fresh in vitro brain tissue undergoing large deformations. To address the paucity of data regarding the accelerations experienced by a child’s head during falls, shakes and inflicted impacts, we built an instrumented doll, and found that because a newborn’s neck is compliant, impacts on firm surfaces can cause a rebound that may produce severe brain injuries.

In addition, our studies regarding the rate-dependent and age-dependent mechanical properties of the skull indicate that injuries resulting from head impacts may be exacerbated in infants by the properties of the skull. Previous information available regarding the deformable nature of the infant skull was limited to quasi-static loads experienced during vaginal delivery and slow crushing events, but our data identified that the skull softens during rapid distortions, offering little protection to the young brain during impact.

In a field filled with social, medical, and legal controversy, our research program is one of the few in the world providing objective bioengineering data regarding injury mechanisms in young children. By increasing our understanding of how head injuries occur in children, this crucial information enables engineers to design safer protective equipment (e.g. car seats, helmets) for children and provides physicians with tools to assist them in the diagnosis and treatment of violence-related and unintentional head injuries in children.

Email: margulie@seas.upenn.edu

Dr. David Meaney

Molecular neuroengineering: Investigate the effect of mechanical forces on neurons and astrocytes. Identifying the mechanosensitive receptors that are activated in mechanotransduction. Relating these mechanotransduction events to gene expression changes within single cells, and identifying the important regulatory genes expressed in neurons following mechanical injury.

A particular focus is now on RNA binding proteins and their role of localizing and targeting mRNA within neurons and astrocytes. These experiemental tools are combined with computational methods to model the receptor-mediated changes in neurons and astrocytes afetr traumatic injury, the trafficking of localization of mRNA in dendrites and neurons, and to develop predictive models for dynamic changes as the synaptic level which underlie neural plasticity.

Email: dmeaney@seas.upenn.edu
Webpage: http://www.seas.upenn.edu/~molneuro/

Dr. Robert Neumar

Work focus: Molecular mechanisms ischemic and traumatic neuronal injury. Specific focus is proteolytic signaling cascades.

Email: neumarr@uphs.upenn.edu

Dr. Donald O'Rourke

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: orourked@mail.med.upenn.edu

Dr. Randall Pittman

Primary cultures of neurons and neural cell lines provide model systems to characterize cellular and molecular events in apoptosis/programmed cell death, and polyglutamine neurodegenerative diseases. Cellular, molecular, and biochemical techniques are being used in these studies.

Research projects in the lab include:

• Characterizing signaling pathways controlling the execution phase of apoptosis/programmed cell death.
• Defining the normal and pathological functions of the polyglutamine neurodegenerative ataxin-3.

Email: pittman@pharm.med.upenn.edu
Phone: 898-9736

Dr. David Pleasure

The focus of Dr. Pleasure's laboratory is on the developmental biology of the central nervous system. He has a long-term interest in the regulation of the oligodendroglial lineage by protein growth factors and other environmental factors, and is currently addressing three specific questions in this arena

• How are the numbers of oligodendroglial progenitor cells tailored to fit the need during the period when myelination occurs?
• Why do oligodendroglia express receptor-channels activated by excitatory amino acids, and what is the relevance of these receptor-channels to oligodendroglial death in inflammatory and ischemic disease?
• What is the source of progenitor cells that accounts for oligodendroglial regeneration?

A second area of research in Dr. Pleasure's laboratory deals with the molecular control of regeneration after Wallerian degeneration in the peripheral nervous system.

Email: pleasure@email.chop.edu
Phone: 215-590-2090

Dr. Michael E. Selzer

The focus of Dr. Selzer's laboratory is axonal regeneration in lamprey central nervous system. Unlike axons in the central nervous system of mammals, the axons of the lamprey spinal cord regenerate across a spinal transection, and even grow preferentially through the glial/ependymal scar.

His laboratory is attempting to determine the mechanisms involved in the elongation and guidance of regenerating axons. Electron microscopic analysis of intracellularly labeled growth cones showed that they are packed with neurofilaments (NFs). This is different from growth cones of most neurons studied in dissociated cell culture, which grow much faster than the regenerating spinal axons in lamprey and contain no NFs. Thus one of their goals is to determine whether NFs play a role in the axonal elongation during regeneration in the central nervous system.

They have shown that the lamprey NF is unique in having only one 180 kD NF subunit (NF-180), which has now been cloned and sequenced. However, this subunit does not self-assemble and therefore other intermediate filament proteins may be present and required for assembly. Monoclonal antibodies and sense and antisense riboprobes are being used to study the expression of lamprey NF in injured neurons by immunohistochemistry, in situ hybridization and intracellular injection targeted at manipulating translation or assembly of NF.

In addition, Dr. Selzer is developing methods to image the living axons as they regenerate. The axona are injected with fluorescent tracers and their behavior studied in living spinal cord using timelapse 2-photon laser microscopy. Dr. Selzer is also collaborating with members of the department of radiology to image individual axons and track their regeneration and post-axotomy physiological changes by magnetic resonance imaging.

EM analysis also shows that the growth cones regenerating spinal axons are in disproportionate contact with glial processes. At the margin of an injury, glial cells send thickened, longitudinally oriented fibers into the lesion, forming a glial "scar" and these fibers precede regenerating axons into the wound, suggesting that glial cells may play an important role in guiding the regeneration.

Dr. Selzer's lab is using molecular cloning to study the expression of keratin in glial cells of transected, regenerating spinal cord. Finally, the laboratory is studying the role of developmental guidance molecules of the netrin and semaphorin families in guiding, promoting, or restricting regeneration of spinal cord axons after transection.

Email: selzerm@mail.med.upenn.edu
Phone: 215-662-3396

Dr. Robert Siman

Current work in Dr. Siman's laboratory focuses on molecular mechanisms, markers, and models for neurodegenerative disorders. Modulation of proteolysis as a signal transduction mechanism important for regulation of neuronal morphology and for triggering neuronal apoptosis and necrosis. Amyloid deposition, presenilin biology, and the molecular pathogenesis of Alzheimer's disease. Biomarkers for acute brain damage.

Email: siman@pharm.med.upenn.edu

Dr. Douglas Smith

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.

Phone: 215-898-0881

Dr. John Q. Trojanowski

Research in Dr. Trojanowski's laboratory centers on molecular mechanisms underlying neuron dysfunction, degeneration and death in normal aging and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease, frontotemporal dementias, motor neuron diseases and related disorders.

Email: trojanow@mail.med.upenn.edu

Dr. Deborah Watson

We are interested in defining the signals that recruit endogenous and transplanted neural stem cells towards areas of pathology in the CNS. We create a variety of viral vectors for gene delivery directly into the CNS and via neural stem cell transplants.

In combination with MRI imaging of the transplanted stem cells in live animals, these molecular tools are used to track the location, fate and function of the stem cells. We are evaluating the therapeutic potential of neural stem cells as both replacement neural elements and gene delivery vehicles.

Email: djw3@mail.med.upenn.edu

Dr. John H. Wolfe

This laboratory is investigating somatic gene transfer to the central nervous system, neural stem cells, and molecular mechanisms of neuropathology in lysosomal storage diseases. Animal models of human genetic diseases are used to investigate the molecular fate and efficacy of gene therapy in the CNS.

Three approaches are being investigated:

• Genetically-corrected neural stem cells are transplanted directly into the brain to circumvent the blood-brain barrier. This may be useful for delivering genes to restricted locations or to achieve more general distribution, depending on the age of the recipient and site of the transplant.
• Direct gene transfer into the CNS is being studied using adeno-associated virus and lentivirus vectors (herpesvirus vectors are studies in collaboration with Dr. Fraser). Current studies involve understanding the differences in transduction mediated by variant vius surface proteins (serotypes and pseudotypes).
• Gene transfer to the developing fetus offers unique approaches to the brain as well as the rest of the body before significant pathologic sequelae occur. Using the MPS VII mouse, Dr Wolfe and his colleagues performed the first long-term in vivo correction of disease lesions by vector-mediated gene transfer to hematopoietic stem cells.

His laboratory was also the first to use transplanted neural progenitor cells to correct lesions in the brain after engraftment and differentiation into normal brain structures, and the first to demonstrate that gene transfer in the brain could correct established disease lesions in a storage disease model. These studies are being extended to large animal disease models to study the potential for and barriers to scaling-up gene therapy for treatment of human patients.

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

Dr. John Q. Trojanowski

Research in Dr. Trojanowski's laboratory centers on molecular mechanisms underlying neuron dysfunction, degeneration and death in normal aging and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease, frontotemporal dementias, motor neuron diseases and related disorders.

Email: trojanow@mail.med.upenn.edu