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 central core disease or hypertrophic cardiomyopathy; and from experimental animals. The laboratory is also involved in the following immunological, biochemical and virological studies that examine the usceptibility of the muscle and nerve to immune or viral mediated injuries: (a) study the genetic defect in patients with various metabolic myopathies, mitochondriopathies or spinal muscular atrophies; (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, and the mechanism (apoptosis or necrosis) by which the poliovirus infects, replicates and kills motor neurons or human myotubes in vitro; (d) study the effect of cytokines and lymphokines with emphasis on IL1, IL2, TGFbeta on human myotubes and examine if various immunotherapeutic agents can inhibit their toxic or immunopotentiating effect; (e) study the up-regulation of pre-apoptotic or anti-apoptotic molecules such as fas, fasL, Bcl-2, Bcl-XL, in human muscle in vitro and in vivo; (f) study the toxicity of nucleoside analogues, such as AZT and FIAU to muscle mitochondria to the mitochondrial oxidative phosphorylation and the mit. DNA by applying these agents to human muscle in culture; and (g) 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 effect of L-carnitine in reversing or improving the nucleoside-induced neuromuscular toxicity in the experimental animals or in tissue cultures; (iii) the inflammatory response in TGF-b knock-out mice; and (iv) the T cell receptor and cytokine profile in mdx mice treated with an adenovirus vector carrying the dystrophin gene.