This grant, first funded in 1981, is a continuing exploration of the hypothesis that (a) endothelial cell (EC) surface proteins regulate EC interactions with leukocytes;and (b) that inflammatory cytokines like tumor necrosis factor (TNF) exert their effects by altering EC surface protein expression. In the next funding cycle, the specific aims are: (1) to determine the basis of differences in the TNF responsiveness of arterial vs. venous EC, focusing on E-selectin, a TNF induced protein discovered by this grant that mediates leukocyte adhesion;(2) to elucidate the molecular basis of the up regulation of TNF receptor (TNFR) 2 expression on EC caused by changes in oxygen levels (as observed in vivo following ischemia/reperfusion injury);(3) to discover how caveolae and/or lipid rafts can modulate TNF signaling responses of EC, especially the activation of ERK-1,2 and of Akt through TNFR1 as well as ligand-induced TNFR1 internalization and intracellular trafficking;and (4) to discover the mechanisms by which TNF increases protein transit across EC monolayers (""""""""vascular leak""""""""), focusing upon changes in tight junctions and the proteins that form them. These experiments will use a variety of human EC culture systems and analyze these by molecular, immunochemical, morphological and functional approaches. We will also use human mouse chimeric animals to study TNF responses of human EC in vivo. Successful completion of these aims will advance our understanding of TNF responses and may provide the basis for advancing therapeutic approaches to control inflammation.

Public Health Relevance

Tumor necrosis factor (TNF) is a protein secreted by white blood cells that causes inflammation and works, in large part, by acting on the endothelial cells that line blood vessels to change their cell surface from one that repels circulating white blood cells to one that attracts them. This grant will study mechanisms of how TNF causes endothelial cells to change their cell surface. An understanding of these mechanisms can be used to develop new therapies to treat inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease, or diseases with inflammatory components such as atherosclerosis, heart failure or stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036003-25
Application #
7806364
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Gao, Yunling
Project Start
1991-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
25
Fiscal Year
2010
Total Cost
$458,391
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Pierce, Richard W; Merola, Jonathan; Lavik, John Paul et al. (2017) A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome. J Exp Med 214:3497-3505
Al-Lamki, Rafia S; Wang, Jun; Yang, Jun et al. (2016) Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma. Oncotarget 7:24111-24
Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G et al. (2016) Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 1:
Al-Lamki, R S; Lu, W; Manalo, P et al. (2016) Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis. Cell Death Dis 7:e2287
Abrahimi, Parwiz; Chang, William G; Kluger, Martin S et al. (2015) Efficient gene disruption in cultured primary human endothelial cells by CRISPR/Cas9. Circ Res 117:121-8
Clark, Paul R; Kim, Richard K; Pober, Jordan S et al. (2015) Tumor necrosis factor disrupts claudin-5 endothelial tight junction barriers in two distinct NF-?B-dependent phases. PLoS One 10:e0120075
Pober, Jordan S; Sessa, William C (2014) Inflammation and the blood microvascular system. Cold Spring Harb Perspect Biol 7:a016345
Wang, Jun; Al-Lamki, Rafia S; Zhu, Xinwang et al. (2014) TL1-A can engage death receptor-3 and activate NF-kappa B in endothelial cells. BMC Nephrol 15:178
Kluger, Martin S; Clark, Paul R; Tellides, George et al. (2013) Claudin-5 controls intercellular barriers of human dermal microvascular but not human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 33:489-500
Al-Lamki, Rafia S; Lu, Wanhua; Wang, Jun et al. (2013) TNF, acting through inducibly expressed TNFR2, drives activation and cell cycle entry of c-Kit+ cardiac stem cells in ischemic heart disease. Stem Cells 31:1881-92

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