NEUROMUSCULAR AND CNS DISEASES AND THEIR EXPERIMENTAL MODELS

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The Section processes more than 100 muscle and nerve biopsies per year for diagnostic and research studies. Examined muscles are from patients with: neuromuscular manifestations related to systemic, autoimmune, viral, metabolic, endocrine or infectious diseases; primary neuromuscular disorders, such as polymyositis, dermatomyositis, inclusion body myositis, neurogenic muscular atrophies, muscular dystrophies, post-polio syndrome, polyneuropathies, mitochondrial encephalomyopathies; patients with biochemical and genetic muscle diseases, such as phosphofructokinase deficiency, hypertrophic cardiomyopathy; or storage myopathies; and from experimental animals. The laboratory is also involved in the following immunological, biochemical and virological studies that examine the susceptibility of the muscle and nerve to immune or viral mediated injuries: (a) study the genetic defect in patients with various metabolic myopathies (with emphasis on phosphofructokinase deficiency), mitochondriopathies and hereditary vacuolar myopathies with emphasis on desmin-storage; (b) study the binding of immunoglobulin from patients with paraproteinemic neuropathies to human glucolipids and glucoproteins and correlate the immunoreactivity with the clinical picture; (c) study the expression of the poliovirus receptor in human muscle in vivo and in vitro, the ability of the poliovirus to infect and replicate in human myotubes and the mechanism (apoptosis or necrosis) by which the poliovirus kills motor neurons; (d) study the effect of cytokines and lymphokines with emphasis on IL1, IL2, TGFbeta on human myotubes and examine in vitro if various immunotherapeutic agents can inhibit their toxic or immunopotentiating effect; (e) study the up-regulation of pro-apoptotic or anti-apoptotic molecules such as fas, fasL, Bcl-2, Bcl-XL, FLIP, human ILP in human muscle in vitro and in vivo; (f) study surface molecules, their mRNA and ligands involved in antigen presentation in the muscle biopsy specimens from patients with autoimmune disorders; g) examine the expression of matrix metalloproteinases using immunocytochemistry, zymography and PCR in the tissues of patients with autoimmune neuropathies and myopathies; h) study the toxicity of nucleoside analogues, such as AZT and FIAU to muscle mitochondria, mitochondrial oxidative phosphorylation and mit. DNA by applying these agents to human muscle in culture. Examination of selective, single fiber, mDNA depletion is considered; i) use animal models to study: (i) the mechanism of AZT-induced mitochondrial myopathy and ddC-induced neurotoxicity by examining the structural, metabolic and functional alterations in the muscle and nerve mitochondria of healthy rats injected with AZT or ddC; (ii) the inflammatory response in TGF-beta double knock-out mice and the role of various integrins; and (iii) the T cell receptor and cytokine profile in mdx mice treated with an adenovirus vector carrying the dystrophin gene.