Neurology Laboratories

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. For more information about Dr. George's research, go to:

http://www.med.wayne.edu/neurology/basic_research/Labs/Ted_George/Axon_Biology_Lab.htm

Edwin B. George, M.D., Ph.D.

Back to Neurology Laboratories List

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, go to:

http://www.med.wayne.edu/neurology/basic_research/Labs/maiese/homepage.html

Paula Dore-Duffy, Ph.D.

Kenneth Maiese, M.D.

Back to Neurology Laboratories List

Basic science studies in diabetic peripheral neuropathy include ongoing collaborations between Dr. Anders Sima, a leader in the field of diabetic complications, and Drs. Lisak and Skundric. In the area of PNS, Dr Skundric's lab is focused on studying the role of neuropoietic cytokines in Schwann cell (SC) - axonal communication and in degeneration of the peripheral nerve. Research has found that proinflammatory cytokines, IL-1, IL-6 and TNFa, produced by SC, have an important role in development of neurologic complications in type I diabetes. In diabetic peripheral nerve, production of these cytokines by SC is altered as a result of metabolic and enzymatic changes induced by hyperglycemia. Cytokines themselves by autocrine or paracrine regulation modulate the expression of Na+ channels, Na+/K+ ATPase, cell adhesion molecules, apoptosis related proteins in diabetic peripheral nerve. Drs Lisak and Skundric are studying role of neuropoietic cytokines in regulation of autoimmune and inflammatory neuropathies. For more information about Dr. Skundric's research, go to:

http://myprofile.cos.com/dusanka

Robert P. Lisak, M.D.

Dusanka Skundric, M.D., Ph.D.

Back to Neurology Laboratories List

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 Aactivity-dependent@ human epilepsy genes that will develop new directions to understand and treat this disease. For more information about Dr. Loeb's research, go to:

http://cmmg.biosci.wayne.edu/jloeb/index.html

Jeffrey A. Loeb, M.D., Ph.D.

Back to Neurology Laboratories List

Dr. Benson is a fellowship trained behavioral neurologist with a strong emphasis on neuroimaging using MRI. His basic science interests include:

Functional neuroanatomy underying speech and language: Goal is to use functional MRI (fMRI) to map speech perception in the brains of normals (non-aphasic adults and adolescents) and aphasic patients.

Inducing adaptive neuroplasticity in aphasic and hemiparetic stroke patients using focal cortical electromagnetic stimulation. Funded studies include using electrical stimulation via implanted epidural electrode in hemiparetic patients and transcranial electrical stimulation in aphasic patients. fMRI to follow brain activation before and after treatment to be correlated with treatment response.

MRI of traumatic head injury: in collaboration with Dept. of Radiology, Engineering, Neuropsychology, Psychiatry, Dr. Benson is working to develop an MRI based method of diagnosing and prognosticating the outcome of traumatic brain injury. Researchers will rely on the recently developed MRI methods of susceptibility weighted imaging (blood sensitive), perfusion, diffusion (ischemia, edema), diffusion tensor imaging (white matter shearing) and MR spectroscopy (metabolic state). Each of these imaging techniques yields important and non-redundant information bearing on injury and recovery.

Dr. Benson also investigates pre-surgical mapping of language and memory in refractory epileptics and brain tumor patients and future research includes the functional imaging of dementia.

Randall R. Benson, M.D.

Back to Neurology Laboratories List

There are ongoing basic science studies on the immune system in MS and its experimental model, experimental autoimmune encephalomyelitis (EAE). These include the cellular and molecular mechanisms of disease pathogenesis, and the role of CNS endothelial cells and pericytes in EAE. Drs. Dore-Duffy, Lisak, Ragheb, and Skundric are all involved in these studies. Drs. Ragheb and Lisak study the immunopathogenesis of MS and the effects of immunotherapeutic drugs on cellular and molecular immune pathways. Drs. Skundric and Lisak study the role of chemokines in EAE and MS . Dr Skundric studies molecular and immune mechanisms that regulate relapsing experimental autoimmune encephalomyelitis (EAE). Her laboratory developed a novel model of relapsing-remitting EAE in response to H-2 b restricted encephalitogenic epitope of myelin oligodendrocyte protein (MOG 35-55 ) in (B6 x SJL) F1 (H-2 b/s ) mice, which closely resembles human pathology. They utilize this EAE model to study immune regulation of encephalitogenic T cell homing, immune modulation of CD4+Th1 effector functions, and interactions between autoagressive T lymphocytes and oligodendrocytes. They found that lymphocyte chemoattractant cytokine IL-16 has an important role in regulation of relapsing disease in H-2 b/s mice, as therapy with an IL-16 neutralizing antibody improved paralysis, impeded CD4+ T cell infiltration and reduced demyelination and axonal degeneration. For more information about Dr. Skundric's work, go to:

http://myprofile.cos.com/dusanka

Dr. Dore-Duffy examines the role of inflammatory cytokines and chemokines in activating CNS endothelial cells and pericytes.

Dr. Loeb's laboratory works to decipher the molecular communication within nerves. They are examining how regulatory factors called neuregulins are released from the axons in response to signals they see from their supporting cells, the glia. Understanding the basic mechanisms of axoglial communication during development will give us new clues and treatment strategies in human diseases of peripheral and central nerves such as peripheral neuropathies, multiple sclerosis, and nerve and brain injuries. For more information about Dr. Loeb's research, go to:

http://cmmg.biosci.wayne.edu/jloeb/index.html

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. For more information about Dr. Benjamins' research, go to:

http://www.med.wayne.edu/neurology/basic_research/Labs/Benjamins/GlialLaboratory.html

A related project in collaboration with Dr. Robert Lisak utilizes gene arrays to analyze effects of cytokines on growth factor production by oligodendrocytes in the CNS and Schwann cells in the PNS. This project with Dr. Lisak examines the effects of cytokines on glial cell injury and protection. The long-term objective is to identify strategies for protecting myelin-producing glia from damage and optimizing myelin repair in white matter injury associated with diseases such as multiple sclerosis or with the sequelae of stroke or trauma.

Dr. Lisak specializes in the treatment of patients with Multiple Sclerosis and Myasthenia Gravis. His laboratory interests include studying the effects of cytokines, which are the protein messengers produced by immune cells that invade the brain the Multiple Sclerosis. He is also looking at the effects of these substances on development and survival of the myelin producing nerve cells. Most recently he has been studying these responses using gene technology. His goal is to stop or prevent the damage caused when the immune cells invade the brain and try to destroy myelin.

Robert P. Lisak, M.D.	Joyce A. Benjamins, Ph.D.
Paula Dore-Duffy, Ph.D.	Samia Ragheb, Ph.D.
Dusanka Skundric, M.D., Ph.D.	Jeffery A. Loeb, M.D., Ph.D.

Back to Neurology Laboratories List

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. For more information, go to:

CMT clinic

A second disease this studied by this group is Pelizaeus-Merzbacher disease (PMD), an inherited disorder of central myelin caused by mutation in the gene encoding proteolipid protein (PLP), the major CNS myelin protein. Dr. Garbern is the director of a unique clinic evaluating patients with PMD. Work in the laboratory is focused mainly on how mutations in PLP, expressed only in oligodendrocytes, alters the function of the axons myelinated by them. Dr. Garbern and his colleagues have found that absence of PLP expression leads to axonal degeneration, and their work is directed toward understanding the molecular and cellular basis of this effect. For more information about the PMD clinic, go to:

PMD information

A third disease studied in this group is multiple sclerosis (MS). Dr. Kamholz is involved in a study of the genetics of MS in African American patients, which will lead to further understanding of the cause of MS in all ethnic groups. Work in the laboratory is primarily focused on the role of PLP expression in causing axonal damage in patients with MS. Decreased expression of PLP in MS lesions might be responsible for the axonal degeneration known to cause patient disability MS, and further understanding of this problem will lead to new treatments for patients.

Dr. Loeb's laboratory studies the early molecular events regulating the formation of synapses in the developing nervous system. Their 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 they 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. In their studies, they 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 their missions is to take the principles learned from early development and apply these toward understanding and treating diseases of the nervous system including neuropathy, ALS, and multiple sclerosis. For further information about Dr. Loeb's research, go to:

http://cmmg.biosci.wayne.edu/jloeb/index.html

John Kamholz, M.D., Ph.D.	Michael Shy, M.D.	Jun Li, M.D., Ph.D.
James Y. Garbern, M.D., Ph.D.	Karen Krajewski M.S., CGC	Jeffrey A. Loeb, M.D., Ph.D.

Back to Neurology Laboratories List

Within the Division of Pediatric Neurology, 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. For more information, go to:

http://peds.med.wayne.edu/departments/NEUR.asp?DIV_ID=NEUR&DIV_ID2=NEUR&DIV_ID3=NEUR

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. For more information about Dr. Gow’s research, go to:

http://cmmg.biosci.wayne.edu/Faculty/gow/gow.htm

A. H. M. Mabbubul Huq, M.D., Ph.D., FRCPC         Gyula Acsadi, M.D., Ph.D.
Alex Gow, Ph.D.

Back to Neurology Laboratories List