The ultimate goal of this proposed research is to elucidate the mechanism of the pathogenesis of Reye's syndrome (RS). The central theme of our research is to gain deeper insight into the site(s) of regulation, at the molecular level, of mitochondrial disorders in Reye's syndrome. We propose to employ both the in vitro and in vivo approaches to further characterize the action of RS-plasma on mitochondrial structure and function, with allantoin plus calcium ion as the key components responsible for the mitochondrial injuries being our working hypothesis. We plan to use the following approaches: (I). To elucidate the action of RS-plasma, on mitochondrial metabolism by continued investigation of: a. the effects fo RS-plasma, allantoin plus and minus calcium ion on mitochondrial functions in isolated mitochondrial preparations from liver, skeletal muscle and heart; b. the possible origin of allantoin and its content in RS-plasma. (II). To further characterize the action of RS-plasma and allantoin plus and minus calcium ion on membrane permeability of isolated hepatocytes and mitochondrial preparations. (III). To identify the site(s) of structural alterations induced by various treatments in RS-patients and animal model, in isolated hepatocytes and mitochondrial preparations by means of ultrastructural examination in parallel with the biochemical studies. (IV). To develop an animal model in which to test the effects of allantoin plus and minus calcium ion in an in vivo system. Correlation of the clinical parameters together with the biochemical and ultrastructural studies will be made. Knowledge derived from these studies will contribute to our understanding of the pathogenesis of Reye's syndrome at the molecular level and will, in turn, lead to the development of improved therapeutic procedures.
