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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL087123-10
Application #
9207786
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
2006-12-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
10
Fiscal Year
2017
Total Cost
$2,103,765
Indirect Cost
$788,912
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Tabas, Ira; Lichtman, Andrew H (2017) Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 47:621-634
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
Cinti, Francesca; Bouchi, Ryotaro; Kim-Muller, Ja Young et al. (2016) Evidence of ?-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab 101:1044-54
Libby, Peter; Bornfeldt, Karin E; Tall, Alan R (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118:531-4
Kim-Muller, Ja Young; Kim, Young Jung R; Fan, Jason et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in ?-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem 291:10162-72
Ozcan, Lale; Ghorpade, Devram S; Zheng, Ze et al. (2016) Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep 15:2214-2225
Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859
Tabas, Ira (2016) Heart disease: Death-defying plaque cells. Nature 536:32-3
Westerterp, Marit; Wang, Nan; Tall, Alan R (2016) High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization. Circ Res 119:13-5
Ozcan, L; Tabas, I (2016) Calcium signalling and ER stress in insulin resistance and atherosclerosis. J Intern Med 280:457-464

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