CLINICAL RESEARCH CENTER FOR NEUROMUSCULAR DISEASE

DESCRIPTION (provided by applicant) This Clinical Research Center, now in Year 27, has been concerned with human neuromuscular diseases. The broad objective is to elucidate the etiology and pathogenesis of these disorders, in order to either devise rational treatments for presently untreatable conditions or provide information that could guide sound genetic counseling. The emphasis has shifted during different periods of the grant, but we have always concentrated on clinically relevant research. The current program includes two themes: (i) amyotrophic lateral sclerosis (ALS); and (ii) mitochondrial encephalomyopathies. Although ALS is a new theme, Center investigators have been active in both fields and most of them have been collaborating for years. There are four projects. Drs. Hirano and Bonilla will extend pioneer work on mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) by: (i) better defining morphological and biochemical changes in postmortem tissues; (ii) documenting the extent and tissue distribution of mitochondrial DNA deletions, depletion, and point mutations; (iii) studying the effects of thymidine phosphorylase (TP) deficiency in cultured fibroblasts; and (iv) studying the clinical and biochemical consequences of TP deficiency in knockout mice. Dr. Przedborski will investigate the role of oxidative damage and inflammation in the pathogenesis of familial ALS using transgenic mice expressing the G93A mutation in the Cu/Zn superoxide dismutase (SOD). Drs. Beal and Mitsumoto will investigate mitochondrial dysfunction in ALS and its potential etiological role using both human samples and available ALS transgenic mice. Drs. Schon and Davidson will look for nuclear COX-assembly gene defects in patients with different forms of COX deficiency using microcell-mediated chromosomal transfer or rodent-human somatic cell hybrid panels and looking for functional complementation. Two Core Units, an Administrative Core (DiMauro and Mitsumoto) and a Clinical Core (Mitsumoto and DiMauro), will provide direction, administration, external and internal consultation, clinical coordination, and shared technical service to the project as a whole.