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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL098055-04S1
Application #
8724891
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2015-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$557,739
Indirect Cost
$227,716
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304
Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8
Gulshan, Kailash; Brubaker, Gregory; Conger, Heather et al. (2016) PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. Circ Res 119:827-38
Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis et al. (2016) Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo. Elife 5:
Iqbal, Asif J; Fisher, Edward A; Greaves, David R (2016) Inflammation-a Critical Appreciation of the Role of Myeloid Cells. Microbiol Spectr 4:
Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115
Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558

Showing the most recent 10 out of 134 publications