The overall goals of this continuing Program Project are to develop a better understanding of the mechanisms linking oxidation and inflammation to cardiovascular disease. Each project focuses on elucidating mechanisms of how distinct yet interconnecting pathways of oxidation operative during inflammation contribute to cardiovascular disease and disrupt homeostatic mechanisms normally responsible for resolution of inflammatory responses. The Program Project is led by a team of highly productive experts and comprised of 3 interrelated projects and 4 cores. Project 1 focuses on the leukocyte-derived heme protein myeloperoxidase (MPO), an enzyme that can catalytically consume nitric oxide and is a critical participant in oxidative and inflammatory injury during atherosclerosis. Genetic, biophysical and clinical studies are proposed to further define mechanisms responsible for regulating MPO activity in vivo and their links to development of cardiovascular disease. Project 2 is thematically linked to Projects 1 and 3, and explores both the role of the ribosomai protein L13a in post transcriptional resolution of inflammatory gene expression, and the inhibition in this inflammation response """"""""off switch"""""""" by the actions of myeloperoxidaseand nitric oxide-derived oxidants. The theme of inflammation and oxidation continues in Project 3, which will study mechanisms through which endothelial nitric oxide synthase becomes """"""""uncoupled"""""""", leading to increased oxidant production, endothelial dysfunction and cardiovascular disease. Three scientific cores (Mass Spectrometry;Biophysical and Computational Chemistry;and Protein Engineering and Expression) and an Administrative Core provide multiproject support, expertise and service in a cost-effective manner, significantly strengthening the entire research program. The Program Project also benefits from shared access to a large repository of clinical samples and connecting database from well-characterized patients who underwent elective cardiac catheterization and for whom long-term follow-up is available. The proposed Program Project will yield a greater understanding of the role of oxidation in normal physiologic processes and disease pathogenesis. It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy.

Public Health Relevance

The overall goal of this Program Project is to develop a better understanding of the mechanisms linking oxidation and inflammation to cardiovascular disease. Special emphasis is placed on studies of specific enzymes found in white blood cells and cells of the artery wall involved in nitric oxide synthesis, their role in causing vascular injury, as well as mechanisms for inhibiting resolution of vascular inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076491-08
Application #
8217166
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
2004-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$1,832,428
Indirect Cost
$628,912
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Szpak, Dorota; Izem, Lahoucine; Verbovetskiy, Dmitriy et al. (2018) ?M?2 Is Antiatherogenic in Female but Not Male Mice. J Immunol 200:2426-2438
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
Li, Xinmin S; Wang, Zeneng; Cajka, Tomas et al. (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI Insight 3:
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2018) The GAIT translational control system. Wiley Interdiscip Rev RNA 9:
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
Brown, J Mark; Hazen, Stanley L (2018) Microbial modulation of cardiovascular disease. Nat Rev Microbiol 16:171-181
Hirbawi, Jamila; Bialkowska, Katarzyna; Bledzka, Kamila M et al. (2017) The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation. J Biol Chem 292:14258-14269
Plow, Edward F (2017) An enlightening year in vascular biology. Curr Opin Hematol 24:222-223
Brown, J Mark; Hazen, Stanley L (2017) Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery. J Biol Chem 292:8560-8568

Showing the most recent 10 out of 271 publications