The goal of this Program is to develop a mechanistic understanding of the link between lipid oxidation and vascular pathology. The senior research team is a highly interactive multidisciplinary group with a broad range of shared expertise, including cell biology, chemical biology, biochemistry, and immunology. The 4 interrelated projects will test the hypothesis that oxidation of phospholipids in lipoproteins and cell membranes creates specific ligands for vascular cell receptors, transporters, and enzymes that then drastically alter cellular function and contribute to the pathogenesis of inflammatory diseases, including atherosclerosis. Project 1 will combine biophysical and clinical studies to define the chemical structures, biophysical properties, and oxidative pathways that participate in the formation, decay, and receptor binding activities of a novel family of specific oxidized phospholipid ligands of the Class B scavenger receptor CD36. This project will also assess the clinical relevance of specific oxidized phospholipids in human athero-sclerosis. Project 2 will determine how vascular cells clear biologically active and toxic components of oxLDL by defining the fate of extracellular oxidized phospholipids, characterizing transporters and transport mechanisms of oxidized phospholipids, and determining signaling pathways connecting oxLDL and phospholipids to cell viability. Project 3 will define complex mechanisms that regulate expression and activity of monocyte/macrophage 15- lipoxygenase, the enzyme responsible for producing 13-HPODE, an oxidation product of linoleic acid and a prominent oxidized lipid found in atheroma. Project 4 will define vascular cell signaling pathways initiated by binding of specific oxidized phospholipids to CD36, focusing on how this signaling cascade modulates foam cell formation, inflammatory responses, and metabolic pathways. An Administrative Core and 2 scientific cores, """"""""Analytic and Synthetic Chemistry"""""""" and """"""""Monocyte/Macrophage Cell Biology"""""""" strengthen the Program by providing well characterized, uniform-quality cellular, animal, and chemical reagents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL087018-04
Application #
7841709
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Fleg, Jerome
Project Start
2007-08-06
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$2,281,238
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Chen, Yiliang; Huang, Wenxin; Yang, Moua et al. (2017) Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. Arterioscler Thromb Vasc Biol 37:1462-1469
Silverstein, Roy L (2017) Linking Metabolic Dysfunction to Atherosclerosis Via Activation of Macrophage CD36 Gene Transcription by Retinol Binding Protein-4. Circulation 135:1355-1356
Ramakrishnan, Devi Prasadh; Hajj-Ali, Rula A; Chen, Yiliang et al. (2016) Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation. Arterioscler Thromb Vasc Biol 36:534-44
Gupta, Nilaksh; Li, Wei; McIntyre, Thomas M (2015) Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. Arterioscler Thromb Vasc Biol 35:2657-66
Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang et al. (2015) Acrolein impairs the cholesterol transport functions of high density lipoproteins. PLoS One 10:e0123138
Chen, Yiliang; Kennedy, David J; Ramakrishnan, Devi Prasadh et al. (2015) Oxidized LDL-bound CD36 recruits an Na?/K?-ATPase-Lyn complex in macrophages that promotes atherosclerosis. Sci Signal 8:ra91
Cathcart, Martha K; Bhattacharjee, Ashish (2014) Monoamine oxidase A (MAO-A): a signature marker of alternatively activated monocytes/macrophages. Inflamm Cell Signal 1:
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Gupta, Nilaksh; Li, Wei; Willard, Belinda et al. (2014) Proteasome proteolysis supports stimulated platelet function and thrombosis. Arterioscler Thromb Vasc Biol 34:160-8
Srikanthan, S; Li, W; Silverstein, R L et al. (2014) Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J Thromb Haemost 12:1906-17

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