The program project addresses the pathogenesis of the clinical termed Reye Syndrome (RS). This syndrome is characterized by metabolic encephalopathy and hepatic dysfunction. Our studies have identified some individuals with RS as having disorders of fatty acid oxidation. These studies have also identified patients who, though not clinically resembling RS, share with it biochemical and other similarities. A major focus of the continuing proposal is to utilize fibroblasts from RS patients with well characterized disorders of fatty acid oxidation, neuronal and astrocyte cell cultures and animal models in order to elucidate the mechanisms of the metabolic encephalopathy and hepatic dysfunction in RS. Project IA comprises a Clinical and Administrative Core and Project IB is a new Biochemistry Core established to provide well characterized cell culture material for four projects, together with analytical and biochemical analyses for all projects. Project II addresses the pathogenesis of hyperammonemic encephalopathy, utilizing purified cultures of astrocytes and neurons as specific models of intracerebral metabolism and cultured fibroblasts to identify abnormalities in ammonia metabolism secondary to genetic defects of mitochondrial beta-oxidation. These studies feature the use of the stable isotopes, 15N, which is then quantified by GC- mass spectrometry. Projects III and IV examine and define the mechanisms of impaired fatty acid oxidation (FAO) and cellular injury in RS and in the genetic disorders which resemble RS. Proposals in Project III seek to identify acylcarnitine esters in patients with disorders of FAO and to explore the interaction between fatty acid oxidation and carnitine homeostasis or transport in cell culture and in animal models. In Project IV, the specific enzymatic defects in FAO will be identified and characterized, and the molecular genetics of these mitrochondrial defects will be determined. Project V addresses the role of peroxisomes in the production of the unusual fatty acids identified under the conditions of impaired FAO or in RS and explores the possibility that defects of membrane receptor function may lead to altered FAO in RS. Project VI elucidates the mechanism for an endothelial-cell macrophage interaction which initiates the secretion of products central to the processes which result in hepatocellular injury. Specific proposals will address the etiology of the biochemical derangements of hepatic energy demonstrated in this model.
