The Program Project will address the pathogenesis of Reye's Syndrome (RS). It is composed of four sections and six projects. The first section, Project IA, is a central clinical core within Children's Hospital of Philadelphia, a large children's referral hospital, with a referral base of 12 million; as well as core electron microscopic facilities. The research proposals are contained in Sections II, III, and IV. Section II - Project II - The role of ammonia toxicity in the pathogenesis of (RS) will be addressed using in vivo and in vitro models, and newly developed GC-mass spectrometric techniques. Section III - Projects III, IV, V - Energy metabolism in RS - This section contains three projects which examine the mechanisms of impaired fatty acid oxidation in RS and in genetic forms of fatty acid oxidation which mimic RS. Abnormalities of carnitine metabolism as a primary or an acquired defect will be specifically addressed. The genetic defects of fatty acid oxidation will be further elucidated in vitro using fibroblasts and leukocytes, permitting detailed characterization of the genetics and biochemistry of the known genetic defects. Lastly, these tissues will be utilized to address the process by which distinctive accumulation of Acyl-CoA intermediates serve to locate the site of the defects in fatty acid oxidation. Section IV - Project VI - Studies of immunological and reticuloendothelial systems in RS will examine the hypothesis that altered clearance of endotoxin by the reticuloendothelial system, or that activation of the macrophage may initiate changes which lead to mitochondrial damage and abnormalities characteristic of RS.
