Inflammation is a process essential for host defense and tissue repair. However, exuberant defense may cause pathogenic changes leading to vascular diseases such as atherosclerosis. The primary goal of this renewal application is to build from the previous granting period to characterize proinflammatory cytokines such as TNF-activated signal transduction in vascular endothelial cells (EC) to identify novel JNK activation pathways in inflammation. TNF signaling events are bimodal: survival signal via activation of NF-kappaB, inflammation/apoptosis via activation of JNK. The major hypothesis of this proposal is that inhibition of JNK without disruption of NF-kappaB activation provides a valid approach for anti-inflammatory therapy. We have identified several molecules including ASK1 and AlP1 specifically mediating JNK (but not NF-kappaB) signaling. Moreover, atheroprotective laminar flow inhibits TNF-induced ASK1-JNK and gene expression of proinflammatory molecules. We have cloned a novel Ras-GAP protein (ALP1) and demonstrated that AlP1 is critical for TNF-induced ASK1-JNK activation and is a new target of atheroprotective laminar flow. The specific hypotheses to be investigated are: AlP1 specifies TRAF2 for ASK1-JNK activation; AlP1 is a flow sensor in prevention of TNF-induced ASK1-JNK activation.
Three specific aims are proposed: 1) To determine the roles of AlP1 in TNF-induced JNK pathway. 2) To define the roles of AlP1 in flow-mediated inhibition on TNF-induced ASKI/JNK activation. 3) To determine the role of AlP1 in atherosclerosis in apoE- /- mouse model. This proposal should provide candidate proteins that are specific or unique targets for TNF-mediated inflammatory events and facilitate development of new therapeutic approaches to control inflammation in various disease settings.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL065978-05
Application #
6775346
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
2000-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$402,400
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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