The research goal is to study the role of fatty acid binding protein (FABP), in fatty acid metabolism in the normal, ischemic and hypoxic heart as an example of the molecular basis of cellular injury. Fatty acids and their metabolites have been implicated in membrane damage and enzyme inhibition during ischemia secondary to their amphipathic nature. They are also thought to be arrhythmogenic. The objective of study is to test the hypothesis that FABP has a critical role in fatty acid metabolism, and that under ischemic conditions, failure of binding of fatty acids to FABP due to decreased systhesis, increased destruction or altered cellular conditions is the critical event leading to an increase in cytosolic unbound fatty acids and their toxic metabolism. Phase I will be devoted to isolating and characterizing cardiac FABP, developing antibodies to establish and Enzyme-Linked Immunosorbent Assay (ELISA), and studying the localization and turnover of FABP in the heart. During Phase II the function of FABP under normal, hypoxic and ischemic conditions will be studied in the working isolated perfused heart and in vivo. Coronary occlusion in the anesthetized, open-chested rabbit will be used as the in vivo model and plasma and myocardial tissue FABP levels will be measured by the ELISA assay developed in Phase I. This work will provide new information about the underlying molecular events which precipitate arrhythmias and the biochemistry of myocardial ischemia. The second goal of this proposal is for the PI to learn basic biochemical skills including the development and application of immunologic methodologies under the direction of an established biochemist.
| Knowlton, A A; Connelly, C M; Romo, G M et al. (1992) Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion. J Clin Invest 89:1060-8 |
| Knowlton, A A; Eberli, F R; Brecher, P et al. (1991) A single myocardial stretch or decreased systolic fiber shortening stimulates the expression of heat shock protein 70 in the isolated, erythrocyte-perfused rabbit heart. J Clin Invest 88:2018-25 |
| Knowlton, A A; Brecher, P; Apstein, C S (1991) Rapid expression of heat shock protein in the rabbit after brief cardiac ischemia. J Clin Invest 87:139-47 |
| Knowlton, A A; Burrier, R E; Brecher, P (1989) Rabbit heart fatty acid-binding protein. Isolation, characterization, and application of a monoclonal antibody. Circ Res 65:981-8 |
| Knowlton, A A; Apstein, C S; Saouf, R et al. (1989) Leakage of heart fatty acid binding protein with ischemia and reperfusion in the rat. J Mol Cell Cardiol 21:577-83 |
