The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complication, atherosclerotic cardiovascular disease (CVD). Thus, there is great interest in understanding the role of insulin resistance in both hepatic dyslipidemia, which triggers and maintains atherosclerosis, and in atherogenic events occurring in the plaque cells themselves. The proposed PPG will bring together experts in these different areas working towards a common goal and with a proven record of success over the last 5 years of funding. The overall theme of the PPG is to elucidate novel signal transduction pathways in the liver and in lesional macrophages (Mfs) and endothelial cells (ECs) that contribute to the dyslipidemia and accelerated atherosclerotic lesion progression in insulin-resistant states. In Project 1, Dr. Tabas will focus on the enzyme CaMKII, which has a critical role in (a) both basal and insulin resistance-exacerbated apoptosis of endoplasmic reticulum (ER)-stressed Mfs, which leads to plaque necrosis; and (b) in hepatic derived metabolic disturbances, including dyslipidemia and alterations in FoxO signaling, in obesity and insulin resistance. In Project 2, Dr. Tall will investigate the cellular-molecular mechanisms of hepatic-derived dyslipidemia in insulin resistance, with, emphasis on a novel mTORC1-Sortilin1 pathway that is relevant to recent human genetic studies and, as recent data shows, linked to ER stress and CaMKII. In Project 3, Dr. Accili will focus on vascular ECs as a key site of interaction between insulin resistance and hyperglycemia in atherosclerosis. The emphasis will be on how insulin resistance and hyperglycemia signal through the FoxO proteins to promote atherogenic processes in ECs. Each project will be supported by the Lesion Analysis/Biostatistics Core, in which Dr. Welch's team will provide assistance and expertise in atherosclerosis assays and in biomathematics. The common sub-themes among the projects include: (a) molecules and pathways involved in pro-atherogenic lesional cell dysfunction (Mfs, ECs), including FoxO's, ER stress, CaMKII, mTORC1 (all 3 projects); (b) pathways involved insulin resistance-induced dyslipidemia, including FoxO's, ER stress, mTORC1, Sortilin1, and CaMKII (Projects 1 and 2 in collaboration with Dr. Accili); and (c) mouse models of atherosclerotic lesion development and advanced plaque progression/plaque necrosis (all 3 projects and Core A). The synergistic and highly interactive nature of these projects and the complementary expertise in atherosclerosis and diabetes will enable a unique opportunity to address the emerging epidemic of insulin resistance-associated heart disease.
The most important emerging force behind the leading cause of death world-wide, CVD, is rapidly becoming the epidemic of obesity and insulin resistance. Thus, the future of CVD research and its ultimate goal to develop therapies to lessen the incidence of CVD must place major effort into understanding the cellular and molecular mechanisms linking insulin resistance to CVD, which is the overall goal of this PPG.
|Molusky, Matthew M; Hsieh, Joanne; Lee, Samuel X et al. (2018) Metformin and AMP Kinase Activation Increase Expression of the Sterol Transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) With Potential Antiatherogenic Consequences. Arterioscler Thromb Vasc Biol 38:1493-1503|
|Cai, Bishuang; Kasikara, Canan; Doran, Amanda C et al. (2018) MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal 11:|
|Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709|
|Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44|
|Kraakman, Michael J; Liu, Qiongming; Postigo-Fernandez, Jorge et al. (2018) PPAR? deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects. J Clin Invest 128:2600-2612|
|Ghorpade, Devram S; Ozcan, Lale; Zheng, Ze et al. (2018) Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555:673-677|
|Fredman, Gabrielle; Tabas, Ira (2017) Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 187:1211-1221|
|Doran, Amanda C; Ozcan, Lale; Cai, Bishuang et al. (2017) CAMKII? suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 127:4075-4089|
|Tabas, Ira; Lichtman, Andrew H (2017) Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 47:621-634|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568|
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