Atherogenesis is believed to consist of an intricate series of interrelated events in which blood-borne and cell-derived factors interact with arterial tissue to produce the characteristic pathologic alterations found in atherosclerosis. A central hypothesis that constitutes a major theme of this continuing program is that oxidative processes play a critical role in the changes in vascular cell function that occur during plaque development. The long-term objective of this Program is to elucidate the molecular mechanisms that lead to oxidative reactions in the vessel wall and to define the intracellular pathways and functions that are altered in endothelial cells (EC), smooth muscle cells (SMC), and monocyte/macrophages in response to changes in the cellular milieu, e.g., by oxidized lipids and lipoproteins and by pathophysiological proteins, such as ceruloplasmin and thrombin. Our objective will be approached through four highly focused, but well-integrated, projects. The first project focuses on the underlying mechanisms of both injury to, and proliferation of vascular cells in response to specific lipids of oxidized LDL. Antioxidant blockade of these phenomena will be studied in vitro and in vivo. The antioxidant theme will carry forward into in which the regulation of expression of selenoperoxidases, potent antioxidant enzymes, will be pursued on a molecular level. In a series of mechanistic in vitro and in vivo studied are proposed to address the role of ceruloplasmin in promoting the pro-oxidant state derived growth factor (PDGF) will be studied. The mechanism of induction of PDGF by both thrombin and lysophosphatidylcholine will be pursued. All of the proposed projects represent ongoing studied, and many of the proposed aims represent existing collaborative efforts among investigators of the program project which have developed during the first fourteen years of support. Two continuing scientific cores, Lipoprotein and Cell Culture are proposed to provide multi-project support, expertise and services in a cost-effective manner.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029582-18
Application #
6182961
Study Section
Special Emphasis Panel (ZHL1-PPG-D (M2))
Project Start
1983-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
18
Fiscal Year
2000
Total Cost
$1,412,413
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303
Zhang, Cun-Jin; Wang, Chenhui; Jiang, Meiling et al. (2018) Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nat Commun 9:2745
Han, Juying; Enyindah-Asonye, Gospel; Lin, Feng et al. (2018) CD6 expression has no effect on atherosclerosis in apolipoprotein E-deficient mice. BMC Res Notes 11:229
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2018) The GAIT translational control system. Wiley Interdiscip Rev RNA 9:
Hai, Qimin; Ritchey, Brian; Robinet, Peggy et al. (2018) Quantitative Trait Locus Mapping of Macrophage Cholesterol Metabolism and CRISPR/Cas9 Editing Implicate an ACAT1 Truncation as a Causal Modifier Variant. Arterioscler Thromb Vasc Biol 38:83-91
Eswarappa, Sandeep M; Potdar, Alka A; Sahoo, Sarthak et al. (2018) Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase. J Biol Chem 293:19148-19156
Halawani, Dalia; Gogonea, Valentin; DiDonato, Joseph A et al. (2018) Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains. J Biol Chem 293:8843-8860
Shao, Xinrui; Chen, Siyuan; Yang, Daping et al. (2017) FGF2 cooperates with IL-17 to promote autoimmune inflammation. Sci Rep 7:7024

Showing the most recent 10 out of 276 publications