The overall goals of this new Program Project are to develop a comprehensive structural, mechanistic, functional and clinical understanding of HDL biology and its relationship to atherosclerotic heart disease. The Program is comprised of 3 interrelated Projects that focus on the common theme of investigating various aspects of HDL pathobiology, including asking fundamental questions about HDL particle genesis, maturation, remodeling, structure/function, clinical relevance and use in both novel diagnostic and therapeutic interventions. Each Project also explores the potential biological consequences of HDL alterations in structure and function by specific oxidative modifications that occur within atherosclerotic plaque. Experimental studies proposed in each of the three Projects rely upon collaborative interactions with each of the other Projects. Project 1 proposed studies aimed at providing new insights into how specific structural features of high density lipoprotein (HDL) contribute to its normal biological functions in reverse cholesterol transport, and the role of structurally distinct site-specific oxidative modifications to apoA1 of HDL in altered athero-protective functions of the lipoprotein in humans. Project 2 explores the role of various participants in the RCT processes in atherosclerotic plaque regression, and the role of both HDL, and specific oxidized forms of HDL, in modulating macrophage phenotype and egress within the vessel wall during atherosclerotic plaque regression. Project 3 studies mechanisms through which ABCA1 interacts with apoA1 during HDL biogenesis, specific structural features critical to this process, and the potential utility of oxidant resistant forms of apoA1 as a therapeutic for promoting atherosclerosis plaque regression. Three scientific cores (Mass Spectrometry and Biophysics;Regression of Atherosclerosis;and Recombinant Protein Expression and Molecular Cloning) and an Administrative Core provide multi-project support, expertise and service in a cost-effective manner, significantly strengthening the entire research program. The proposed Program Project will yield greater understanding of specific structural features of HDL and HDL-associated protein complexes critical to cholesterol homeostasis, reverse cholesterol transport, and atherosclerotic plaque progression/regression. It also will identify the functional and clinical impact of site-specific oxidative modifications to HDL that occur within human atheroma. Finally, it may also lead to new diagnostic and therapeutic approaches toward cardiovascular risk assessment and therapy.

Public Health Relevance

The overall goals of this Program Project are to develop a comprehensive structural, mechanistic, functional and clinical understanding of HDL biology and its relationship to atherosclerotic heart disease. The Projects explore both normal functions of HDL in cholesterol homeostasis and plaque regression, as well as in vivo functional consequences of HDL alterations by specific oxidative modifications that occur within human atheroma. New diagnostic and therapeutic interventions are a major focus of investigation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6
Grodin, Justin L; Hammadah, Muhammad; Fan, Yiying et al. (2015) Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure. J Card Fail 21:44-50
Grodin, Justin L; Neale, Sarah; Wu, Yuping et al. (2015) Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med 128:276-82
Tang, W H Wilson; Hazen, Stanley L (2014) The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 124:4204-11
Hartiala, Jaana; Bennett, Brian J; Tang, W H Wilson et al. (2014) Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler Thromb Vasc Biol 34:1307-13
Shao, Zhili; Zhang, Renliang; Shrestha, Kevin et al. (2014) Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure. Am J Cardiol 113:1839-43
Brown, J Mark; Hazen, Stanley L (2014) Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 25:48-53
Duivenvoorden, Raphaƫl; Tang, Jun; Cormode, David P et al. (2014) A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun 5:3065
Feig, Jonathan E; Hewing, Bernd; Smith, Jonathan D et al. (2014) High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Circ Res 114:205-13
Brown, J Mark; Hazen, Stanley L (2014) Seeking a unique lipid signature predicting cardiovascular disease risk. Circulation 129:1799-803

Showing the most recent 10 out of 79 publications