This proposal describes a 5 year training program for developing the skills necessary to become a successful cardiovascular investigator focused on heart failure. The principal investigator has completed MD/PhD training, structured residency training in internal medicine and fellowship training in cardiology and heart failure/transplant at Washington University. He plans to expand his scientific skills to facilitate an integrative career as a physician scientist in the rich academic environment existing at Washington University. The objectives of this research proposal include furthering the principal investigator's experimental technique repertoire, expanding manuscript and grant writing skills, and developing an expertise in the areas of cardiac energy and lipid metabolism to augment his knowledge of inflammatory responses. Dr. Jean Schaffer will mentor the investigator's scientific development. She is a recognized leader in the field of diabetic cardiovascular disease and lipotoxicity, and has an excellent mentoring record. Dr. Dan Kelly, a co-mentor for this proposal is an established investigator in the field of cardiac metabolism in heart failure and diabetes with particular expertise in transcriptional regulation of metabolic and mitochondrial pathways in the heart. An advisory committee consisting of three outstanding physician scientists with relevant expertise will provide additional scientific and career guidance. The proposed research will investigate the molecular crosstalk between Toll-like Receptor (TLR)-mediated inflammation and myocardial metabolism as it pertains to cardiac dysfunction in diabetes and obesity.
Specific aim #1 will define the effects of LPS-induced TLR4-mediated inflammation on myocardial metabolism with an emphasis on inflammatory modulation of the nuclear receptor coactivators PGC-1 and , which function as master regulators of energy metabolism in the heart.
Specific Aim #2 will address the role of TLRs in cardiac lipotoxicity, a key feature of heart failure in diabetics. This will be accomplished by characterizing the cardiac phenotype of the lipotoxic MHC-ACS transgenic mouse bred into TLR4 and TLR4/2 null backgrounds. These results will be complemented with mechanistic studies using TLR4 and TLR2 deficient cells stimulated with the saturated fatty acid palmitate.
Specific Aim #3 will use non-transgenic animal models of diabetes and diet- induced insulin resistance in TLR4-/- and TLR4/2-/- mice to evaluate the role of TLRs in the cardiac phenotype associated with these disease states. Together these studies will help define the contribution of TLR-mediated signaling pathways to cardiac dysfunction in diabetes and will provide significant mechanistic insight into inflammatory-metabolic crosstalk in the myocardium. The Cardiology Division at Washington University provides a supportive environment for training physician- scientists. The diverse scientific expertise of the faculty coupled with the large number of successful physician scientists creates an ideal situation for the principal investigator to develop an independent research program.
Diabetes is an extremely common disease in the U.S. and the number of people with this disorder continues to grow. Patients with diabetes have higher rates of early death than patients without diabetes, largely due to heart disease. In addition heart attacks, diabetes also causes the heart muscle to weaken, leading to heart failure. It is not known precisely why patients with diabetes develop heart failure, but inflammation may play a key role. This proposal will evaluate how the inflammatory response affects the heart and how it may contribute to the heart failure that develops in diabetic patients.
|Weber, Kassandra; Schilling, Joel D (2014) Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem 289:9158-71|
|Schilling, Joel D; Machkovech, Heather M; He, Li et al. (2013) TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell death through a TRIF-dependent pathway. J Immunol 190:1285-96|
|Schilling, Joel D; Machkovech, Heather M; He, Li et al. (2013) Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J Biol Chem 288:2923-32|
|Schilling, Joel; Lai, Ling; Sambandam, Nandakumar et al. (2011) Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor ? coactivator-1 signaling. Circ Heart Fail 4:474-82|
|Schilling, Joel; Kelly, Daniel P (2011) The PGC-1 cascade as a therapeutic target for heart failure. J Mol Cell Cardiol 51:578-83|