Lab Research
Basic Research
Joyce A. Benjamins Ph.D.
Associate Chair, Research
In basic research, several faculty members apply cellular and molecular approaches to fundamental questions of glial and neuron biology, with emphasis on strategies for protection and repair following cell injury. Others focus on mutations in genes involved in myelination to examine the molecular basis of that process, and the signals that mediate interactions between myelin forming cells, axons and neurons in the brain and nerves. Several investigators examine models of immune mediated damage, protection, and disease modification, focusing on blood brain barrier and angiogenesis, cell trafficking in the central nervous system, and the roles of cytokines, chemokines and immune cells in the control of disease in an animal model of multiple sclerosis. Strong programs in myelin diseases, neuromuscular diseases and pediatric epilepsy are translational in nature, with components that are both laboratory-based and patient-based. These programs utilize neurogenetics, neuroimmunology, brain imaging, gene transfer therapy and microarray technology to translate research discoveries to strategies for treatment of disease.
Other basic science studies focus on axonal/glial interactions, particularly myelination, demyelination, and axonal injury. Dr. Joyce Benjamins' research program is focused on myelination and the regulation of myelin gene expression. Dr. Benjamins' laboratory studies the cellular and molecular events leading to the formation and maintenance of the myelin membrane in the central and peripheral nervous systems. Current research is focused on (a) analysis of signaling pathways mediating injury and protection of oligodendroglia, (b) the role of axons in survival of mature oligodendrocytes and maintenance of myelin, and (c) the role of calcium in regulating myelin gene expression and oligodendrocyte survival. To characterize the sequence of events leading from injury to changes in gene expression, her laboratory group apply molecular and immunocytochemical approaches to analyze cultures of mouse oligodendroglia, the N20.1 murine oligodendroglial cell line, and co-cultures of human NT2N neurons and rodent glia. Neurotrophic factors and inhibitors of signaling pathways are studied for their effectiveness in preventing glial death, protecting the ensheathed axons and reinitiating normal myelin production.
The basic science research component of this program is based in two laboratories. Dr. Paula Dore'-Duffy investigates the effects of neuroinjury, particularly traumatic brain injury and hypoxia, on blood/brain barrier function.
Dr. Maiese's research program focuses on neuronal protection in cerebral ischemia. For more information about Dr. Maiese's research, click Dr Maiese's Lab.
Dr. George's Axon Biology Lab studies the role of the axonal cytoskeleton in establishing and maintaining the morphology and connectivity of axons. His research in this area addresses key issues in developmental neurobiology, cell motility, and pathogenesis of axonal and other cytopathies. Studies include research on axonal calcium regulation, calpains and toxicologic mechanisms and an investigation of the expression and distribution of cytoskeletal proteins in growing, regenerating, and mature axons, and an investigation of the mechanisms and modulators of cytoskeleton disassembly during axonal degeneration. These studies are performed in primary explant neuronal tissue cultures of rat and mouse sensory ganglia.
Dr. Loeb's laboratory has two main focuses: the first is to understand the early molecular events regulating the formation of synapses in the developing nervous system. Our analysis centers on how soluble regulatory factors such as the neuregulins and neurotrophins are modulated by neuronal activity to orchestrate neuromuscular synapse formation. Studies underway are examining how neuregulins themselves are regulated during development through their transcription, post translational processing and association with the evolving extracellular matrix and the functional consequences of this regulation on the expression of acetylcholine receptors. Much of what we have learned at the developing synapse is relevant to interactions between neuronal axons and the glia that surround them since the same signaling proteins are used there as well. For our studies, we use both the chicken embryo and transgenic mouse models for in vivo studies that include electroporation to modulate gene expression, as well as many in vitro studies that includes real-time image analysis of living neurons in culture. One of our missions is to take the principles we have learned from early development and apply these toward understanding and treating diseases of the nervous system including multiple sclerosis, where problems in axoglial communication are present.
The second major focus of the laboratory is to understand what leads to the excessive neuronal activity in the human brain that leads to seizures. In this project we are examining human brain tissue that is carefully mapped during epilepsy surgery in order to determine what makes focal regions of human brain epileptic. We are taking a functional genomic approach using sophisticated microarray and bioinformatic technologies to map gene expression patterns to the electrical abnormalities in human epileptic tissues removed during epilepsy surgery. We are identifying a common set of Activity-dependent@ human epilepsy genes that will develop new directions to understand and treat this disease.
Dr. Li is interested in the pathophysiological mechanism of conduction block in hereditary neuropathy with liability to pressure palsies (HNPP). This disease is caused by a heterozygous deletion of chromosome 17p11.2 bearing the peripheral myelin protein 22 (PMP22) gene. Dr. Li has characterized clinical and electrophysiological phenotypes in a large cohort of patients with HNPP. His laboratory is investigating the mechanism of conduction block by using a nerve compression model in both wild type and PMP22 deficient mice. In addition, Dr. Li is developing a skin biopsy technique to evaluate morphological and molecular features of the myelinated nerves in both normal subjects and patients with inherited neuropathies.
The laboratories of Drs. Shy, Garbern and Kamholz are involved in the investigation of disorders of myelination in both the central and peripheral nervous systems. While Dr. Kamholz's research is focused on the role of proteolipid protein in oligodendrocyte differentiation, Dr. Garbern studies markers of CNS white matter damage by MRI in humans and in animal models of CNS disease. Dr. Shy's work in the laboratory is focused mainly on the molecular and cell biology of myelin protein zero (MPZ), the cause of CMT1B, as well as developing the use of skin biopsy as a tool for the evaluation and analysis of demyelinating neuropathy. Dr. Shy and his colleagues have found that MPZ has both a structural and a regulatory role in myelination, and they are attempting to understand the molecular basis of these two functions. In addition, Dr. Shy is the Director of a unique clinic that specializes in the treatment and evaluation of patients with Charcot-Marie-Tooth disease (CMT) from all areas of the US and the world.
John Kamholz MD, PhD is currently a Professor of Neurology, a Professor in the Center for Molecular Medicine and Genetics, and a member of the Graduate Group in Genetics and Molecular Biology. He has served on the Fellowship Committee for the National MS Society, the Medical Advisory Committee of the Muscular Dystrophy Association, and is on the Scientific Advisory Committee for the Pelizaeus-Merzbacher Disease Foundation. He has been an associate editor for the Journal of Neuropathology and Experimental Neurology, and has reviewed papers for a number of peer-reviewed journals including the Annals of Neurology, Journal of Neuroscience, Journal of Neurological Science, Neurology, Journal of Neuroscience Research, Journal of Neurochemistry, Molecular and Cellular Neuroscience, and Biophysics Journal. He was previously a member of the Department of Neurology at the University of Pennsylvania where he was a member of the Neuroscience Institute, the Graduate group in Neuroscience and the Graduate Group in Genetics. Dr. Kamholz research and clinical interests are the regulation and structure of myelin and diseases of the myelin sheath, including multiple sclerosis (MS), a demyelinating disease of the central nervous system, and Charcot-Marie-Tooth disease (CMT), a dysmyelinating disease of the peripheral nervous system. His research include basic studies on the structure and function of the major myelin proteins, myelin protein zero (MPZ) and proteolipid protein (PLP); clinical studies on the phenotype and natural history of patients with inherited diseases of myelin; and clinical trials for the treatment of patient with MS. He is currently funded by the National Institute of Health, the National MS Society, and the Muscular Dystrophy Association.
Dr. Huq directs a neurogenetics clinic; his research interests include identifying genes for autism. Dr. Acsadi investigates the use of gene therapy in a mouse model of spinal muscular dystrophy. Dr. Gow conducts research programs in a molecular mechanisms of neurodegenerative disease, with emphasis on mutations in the PLP gene and on function of axoglial junctions and other intercellular junctions in cochlea and testis.