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. This is because multiple cytokines are involved in the process and each cytokine has multiple effects. For example, TNF signal events use NF?B to promote inflammation and survival whereas activation of the c-Jun N-terminal kinase (JNK) promotes inflammation and apoptosis. We hypothesize that inhibition of JNK without disruption of NF-?B activation provides a valid approach for anti-inflammatory therapy. The cell type that normally limits the inflammatory and atherosclerotic process is the vascular endothelial cell (EC) which can be regulated by proinflammatory (e.g. TNF) and anti-inflammatory mediators (e.g. laminar flow). The major goal of this renewal application is to build from previous two granting periods to characterize novel mediators in JNK regulation. We have identified a unique complex (AIP1 complex) specifically transduces JNK signaling. Our exciting results obtained from AIP1-deficient mice and derived EC generated from our lab support a role of AIP1 in inflammation and ER stress- induced ASK1-JNK activation, and atherosclerosis. We propose the following specific aims: 1). To define the mechanism by which AIP1 activates JNK while inhibits IKK-NF-?B signaling;2) To determine the role of AIP1 in ER stress-induced JNK signaling;3) To determine the role of AIP1 in inflammation and atherosclerosis using animal models. Collectively, these studies should establish the functions of AIP1 for TNF-mediated inflammatory events and flow-mediated protective pathways, and facilitate development of new therapeutic approaches to control atherosclerosis.

Public Health Relevance

Myocardial infarction due to narrowing of arteries manifesting as decreased blood flow remains the leading cause of death in the United States. We will study the effects of a novel scaffolding protein AIP1, on vascular endothelium. Our work may lead to better tests and treatments for atherosclerosis patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065978-10
Application #
7923941
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Hasan, Ahmed AK
Project Start
2000-08-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
10
Fiscal Year
2010
Total Cost
$519,064
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhou, Huanjiao Jenny; Chen, Xiaodong; Huang, Qunhua et al. (2014) AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. Arterioscler Thromb Vasc Biol 34:603-15
Huang, Qunhua; Qin, Lingfeng; Dai, Shengchuan et al. (2013) AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction. Arterioscler Thromb Vasc Biol 33:795-804
Wan, Ting; Xu, Zhe; Zhou, Huanjiao Jenny et al. (2013) Functional analyses of TNFR2 in physiological and pathological retina angiogenesis. Invest Ophthalmol Vis Sci 54:211-21
Jones, Dennis; Li, Yonghao; He, Yun et al. (2012) Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis. Arterioscler Thromb Vasc Biol 32:633-42
Ji, Weidong; Li, Yonghao; Wan, Ting et al. (2012) Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. Arterioscler Thromb Vasc Biol 32:2271-9
Yu, Luyang; Qin, Lingfeng; Zhang, Haifeng et al. (2011) AIP1 prevents graft arteriosclerosis by inhibiting interferon-?-dependent smooth muscle cell proliferation and intimal expansion. Circ Res 109:418-27
Min, Wang; Pober, Jordan S (2011) AIP1 in graft arteriosclerosis. Trends Cardiovasc Med 21:229-33
Wan, Ting; Liu, Ting; Zhang, Haifeng et al. (2010) AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J Biol Chem 285:3750-7
Luo, Yan; Xu, Zhe; Wan, Ting et al. (2010) Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis. Arterioscler Thromb Vasc Biol 30:1307-14
Yu, Luyang; Ji, Weidong; Zhang, Haifeng et al. (2010) SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J Exp Med 207:1183-95

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