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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL013851-44
Application #
7331478
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Przywara, Dennis
Project Start
1997-01-01
Project End
2009-11-30
Budget Start
2007-12-05
Budget End
2009-11-30
Support Year
44
Fiscal Year
2008
Total Cost
$2,234,795
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Peterson, Linda R; Herrero, Pilar; Coggan, Andrew R et al. (2015) Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart. Am J Physiol Heart Circ Physiol 308:H1510-6
Zhou, Dong; Chu, Wenhua; Xu, Jinbin et al. (2014) Synthesis, [ยน?F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography. Bioorg Med Chem 22:1700-7
Gropler, Robert J (2014) Trying to prevent diabetic cardiovascular autonomic neuropathy: more questions than answers. J Nucl Cardiol 21:842-4
Lyons, Matthew R; Peterson, Linda R; McGill, Janet B et al. (2013) Impact of sex on the heart's metabolic and functional responses to diabetic therapies. Am J Physiol Heart Circ Physiol 305:H1584-91
Chen, Delphine L; Zhou, Dong; Chu, Wenhua et al. (2012) Radiolabeled isatin binding to caspase-3 activation induced by anti-Fas antibody. Nucl Med Biol 39:137-44
Lee, Hsiaoju; Chen, Delphine L; Rothfuss, Justin M et al. (2012) Synthesis and evaluation of 18F-labeled PPAR? antagonists. Nucl Med Biol 39:77-87
Herrero, Pilar; Laforest, Richard; Shoghi, Kooresh et al. (2012) Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. J Nucl Med 53:994-1001
Gropler, Robert J (2012) The road connecting obesity and coronary vasomotor function: straight line or U-turn? JACC Cardiovasc Imaging 5:816-8
Solingapuram Sai, Kiran Kumar; Kil, Kun-Eek; Tu, Zhude et al. (2012) Synthesis, radiolabeling and initial in vivo evaluation of [(11)C]KSM-01 for imaging PPAR-? receptors. Bioorg Med Chem Lett 22:6233-6
Cheng, Ju-Chieh Kevin; Shoghi, Kooresh; Laforest, Richard (2012) Quantitative accuracy of MAP reconstruction for dynamic PET imaging in small animals. Med Phys 39:1029-41

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