The ATP Degradation System in Acute Tissue Injury Candidate: The candidate is an assistant professor who has demonstrated clinical and teaching excellence. He has started his full time research training, and requests this grant to complete his development to an independent investigator. Environment: The three co-sponsors as well as the extensive interest at the University of Michigan in acute tissue injury and purine biochemistry provide an exceptional site for research development. Research: Aberrations in various cellular structures and metabolic pathways have been implicated in the pathogenesis of acute tissue injury. One system likely to play a role in acute tissue injury is the adenosine triphosphate (ATP) degradation cascade and its associated enzyme xanthine oxidase. Although the initial insults are different, ATP degradation may be important in the final mechanism of injury in two seemingly separate syndromes: adult respiratory distress syndromes (ARDS) and acute myocardial ischemia. ATP degradation leads to the accumulation of purine intermediates the amount of cellular damage, they may augment or suppress other injury generating systems, and their depletion may limit resynthesis of ATP, thus impairing cellular metabolism. Furthermore, accumulating hypoxanthine and xanthine provide increased substrate for the enzyme xanthine oxidase, which can cause direct tissue damage via reactive oxygen metabolites. I therefore hypothesize that ATP degradation is important in acute tissue injury. I plan to test this hypothesis in two isolated perfused organ systems.
My specific aims are: 1) To examine the role of the ATP degradation system in an acute isolated model of lung injury. I will determine the degree of ATP degradation, the activation of xanthine oxidase, the release of oxygen metabolites and the effect of xanthine oxidase blockade. 2) To study the role of ATP degradation and xanthine oxidase activation in an isolated perfused heart model of acute ischemia injury. I will determine the degree of ATP degradation, the amount of H202 production and the effect of allopurinol administration of these mechanisms. We hope that the resultant improvements in our understanding of ATP degradation, will lead to novel therapeutic interventions in humans with acute myocardial ischemia or ARDS.
