Chronic inflammation is a principal cause of atherosclerosis and other vascular diseases. Inflammation is an orchestrated response to trauma incited by tissue injury or microbial invasion of the host. The inflammatory response is initiated by cytokines that induce cascades of signaling events culminating in the expression of new gene products, some of them toxic to invading organisms. Uncontrolled production or accumulation of inflammatory products can be injurious to the host organism. Mechanisms have evolved that limit the production of these products and permit resolution of the inflammatory response. The central hypothesis of this continuing Program Project is that pro- and anti-inflammatory processes in vascular cells are tightly regulated by endogenous signaling pathways, and their dysregulation contributes to vascular diseases such as atherosclerosis. We will investigate this hypothesis through three highly focused, but well-integrated projects led by a team of accomplished experts in diverse areas of vascular inflammation. In Project 1, Dr. Xiaoxia Li investigates the macrophage signaling pathways initiated by the interleukin-1R (IL-1 receptor)/TLR (Toll-like receptor) superfamily which can lead to either a pro-inflammatory, transcriptional program of gene expression, or an anti-inflammatory, post-transcriptional program. The theme of pro- and anti-inflammation, and also post-transcriptional regulation, continues in Project 2, led by Dr. Paul Fox, which focuses on a distinct post-transcriptional mechanism in monocyte/macrophages in which interferon-??induces phosphorylation- dependent formation of a complex that binds select inflammatory transcripts and inhibits their translation. The goal of Project 3, led by Dr. Paul DiCorleto, is to understand the role of the tumor necrosis factor receptor p75 and the transcription factor HOXA9 in the transcriptional regulation of pro-inflammatory genes in endothelial cells. Three scientific cores (Cell Culture, Atherosclerosis and Lipoprotein Analysis, and Macromolecular Interaction) and an Administration Core will provide multi-project support, expertise, and service in a cost-effective manner, which will significantly strengthen each investigator's research effort.

Public Health Relevance

Inflammation is an underlying cause of vascular diseases such as atherosclerosis. The goal of this Program Project is to understand the basic cellular and molecular mechanisms that induce, sustain, and resolve inflammation in two types of vascular cells - the endothelial cell that lines all blood vessels and the macrophage that specifically enters these vessels as part of the inflammatory response. A deeper understanding of inflammatory pathways is necessary to understand vascular disorders. Knowledge of these pathways may lead to new targets for the development of novel anti-inflammatory therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029582-30
Application #
8448081
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
1997-07-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
30
Fiscal Year
2013
Total Cost
$1,740,097
Indirect Cost
$631,755
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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