The overall goals of this PPG remain largely unchanged, namely to elucidate the pathogenesis graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, in order to develop new strategies to prevent, treat and diagnose this condition. GA is a rapidly progressive stenosis of graft conduit arteries that results in ischemic graft failure. Our general hypothesis is that GA is caused by IFN-gamma, a cytokine made predominantly by certain subsets of T cells. Project by J.S. Pober, project leader, will investigate features of graft endothelial cells that lead to selective recruitment, differentiation and/or activation of host T cells which make IFN-gamma and NO, mediators of GA. Project by Pober will also develop new immunodeficient mouse models for analysis of human GA, exploiting advances in hematopoietic stem cell transplantation and tissue engineering of blood vessels. Project by Min, will investigate how IFN-gamma, acting through SOCS-1, may combine with TNF to produce endothelial dysfunction, an early event in GA. Project by G. Tellides, will investigate how IFN-gamma can cause proliferation and/or death of vascular smooth muscle cells, key processes in vessel remodeling and stenosis. Project by Tellides will also evaluate the contributions of innate immunity and PPAR- gamma signaling to these processes. Project by J.R. Bender, will explore the relationships between IFN-gamma, VEGF and integrin expression and activation in the pathogenesis of GA. Project by Bender will also identify targets and reagents for noninvasive imaging early processes in GA. The Administrative Core (J.S. Pober, core leader) will administer the PPG. The Microsurgery Core (G. Tellides, core leader) will produce immunodeficient mice bearing human xenogeneic or mouse allogeneic arterial segments, models central to this PPG. The Microsurgery Core will also explore the use of immunodeficient rats as the basis for developing a new model for human GA. The Morphometry and Physiology Core (W.C. Sessa, core leader) will provide state-of-the-art analytic tools to evaluate transplanted blood vessel segments. The Apheresis Core (E.L. Snyder, core leader) will conduct leukaphereses of adult human volunteers, providing human lymphocytes and hematopoietic stem cells, crucial reagents for the proposed experiments. If successful, the integrated efforts of the four projects and four cores will not only produce new insights into human GA, but will also increase our understanding of related human arteriopathies such as atherosclerosis and post-procedure restenosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070295-09
Application #
7675374
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Sopko, George
Project Start
2001-09-20
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
9
Fiscal Year
2009
Total Cost
$2,301,198
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kraehling, Jan R; Chidlow, John H; Rajagopal, Chitra et al. (2016) Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nat Commun 7:13516
Siragusa, Mauro; Fröhlich, Florian; Park, Eon Joo et al. (2015) Stromal cell-derived factor 2 is critical for Hsp90-dependent eNOS activation. Sci Signal 8:ra81
Lee, Monica Y; Luciano, Amelia K; Ackah, Eric et al. (2014) Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc Natl Acad Sci U S A 111:12865-70
Pober, Jordan S; Jane-wit, Dan; Qin, Lingfeng et al. (2014) Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy. Arterioscler Thromb Vasc Biol 34:1609-14
Park, Eon Joo; Grabi?ska, Kariona A; Guan, Ziqiang et al. (2014) Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab 20:448-57
Wang, Chen; Yi, Tai; Qin, Lingfeng et al. (2013) Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J Clin Invest 123:1677-93
Yi, Tai; Fogal, Birgit; Hao, Zhengrong et al. (2012) Reperfusion injury intensifies the adaptive human T cell alloresponse in a human-mouse chimeric artery model. Arterioscler Thromb Vasc Biol 32:353-60
Zhang, Jiasheng; Razavian, Mahmoud; Tavakoli, Sina et al. (2012) Molecular imaging of vascular endothelial growth factor receptors in graft arteriosclerosis. Arterioscler Thromb Vasc Biol 32:1849-55
Marin, Ethan P; Derakhshan, Behrad; Lam, TuKiet T et al. (2012) Endothelial cell palmitoylproteomic identifies novel lipid-modified targets and potential substrates for protein acyl transferases. Circ Res 110:1336-44
Forstermann, Ulrich; Sessa, William C (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829-37, 837a-837d

Showing the most recent 10 out of 137 publications