This Program Project Grant application applies positron emission tomography for the in vivo assessment of metabolic pathways in the heart. The approach is to develop new radiopharmaceuticals for the measurement of various receptor or enzyme systems and to evaluate them in animal models of cardiac disease and in human subjects. The three research projects share three cores. In Project 1, new radiopharmaceuticals will be developed to study the up-regulation and down-regulation of receptor or enzyme systems important in cardiac disease. These systems are the PPARalpha and PPARgamma, receptors, the inducible nitric oxide synthase receptor system and caspase-3 and PPAR-1 systems which are important in separating apoptosis from necrosis. Dr. Welch's project will evaluate cardiac metabolism in well-controlled rodent models of diabetes utilizing microPET animal imaging. The microPET imaging will be compared with genetic profiles, echocardiographic assessment of myocardial function and possibly microCT assessment of cardiac function. His project will also evaluate radiopharmaceuticals developed in Project 1 in the appropriate animal models. Dr. Gropler's project has the primary objective of extending studies carried out under this Program Project Grant on the alterations of myocardial substrate metabolism and function in patients with type 1 diabetes mellitus (T1DM) to the study of myocardial substrate metabolism and function in relationship to whole body substrate metabolism in patients with type 2 diabetes mellitus (T2DM). The hypothesis in this project is that in patients with T2DM, treatment strategies that are designed to reach a targeted level of glycemic control and lower levels of plasma non-esterified fatty acids and lipoproteins will be associated with great improvement in myocardial diastolic functions. Patients treated with various therapy regimens will be evaluated. These data in the human population will be compared and contrasted to the data obtained in the rodent models in the previous project. The secondary objective of Dr. Gropler's project is to perform concept studies in humans for the candidate ligands developed in Project 1 and, subsequently evaluated in animal models in. The three research projects will be supported by three Cores; specifically, an administration core, a cyclotron/radiopharmaceutical core, and an instrument/data processing core.
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