The long-term goal of this project is to determine the role of viral pathogens in the development of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune related injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and/or migration from the vessel media to the intima. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of TVS and vascular restenosis following angioplasty as well as atherosclerosis. However, the mechanism(s) involved in the acceleration of vascular disease by HCMV is unknown. In addition we have shown that chemokine receptors encoded by CMV not only induce SMC migration but also decrease the incidence and severity of atherosclerosis when deleted from the virus. In the previous funding period, we have identified unique components of HCMV US28 G-protein coupled receptor (GPCR) signaling pathway that results in SMC migration that is cell specific. Additionally, although US28 binds multiple chemokines, we have observed functional differences between chemokines that bind the viral GPCR. We have also demonstrated that the mouse CMV encoded chemokine receptor M33 is a functional homologue US28. Recently, we have developed a mouse heart transplantation model of TVS that exhibits all of the hallmarks of human disease. We have also shown that MCMV accelerates the progression and severity of TVS in these mice. In this project, we will continue our characterization of the signaling pathways used by US28 and M33 to induce SMC migration examining ligand specificity and functional domains of the GPCRs. We will also use the mouse heart transplantation model of TVS to examine the role of M33 in the development of vascular disease and identify chemokines that are functional in vivo using chemokine knockout mice. Finally, we will use a novel mouse model in conjunction with the heart transplant model to determine the number of cells in the heart allograft infected by MCMV in comparison to the number of cells expressing M33 during the formation of TVS. Completion of the studies proposed in this project will not only confirm a role for CMV chemokine receptors in the development of TVS but also identify chemokines that mediate this process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065754-07
Application #
7083731
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
2000-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
7
Fiscal Year
2006
Total Cost
$368,629
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Smith, M Shane; Goldman, Devorah C; Bailey, Alexis S et al. (2010) Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe 8:284-91
Vomaske, Jennifer; Melnychuk, Ryan M; Smith, Patricia P et al. (2009) Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility. PLoS Pathog 5:e1000304
Baca Jones, Carmen C; Kreklywich, Craig N; Messaoudi, Ilhem et al. (2009) Rat cytomegalovirus infection depletes MHC II in bone marrow derived dendritic cells. Virology 388:78-90
Vomaske, Jennifer; Nelson, J A; Streblow, Daniel N (2009) Human Cytomegalovirus US28: a functionally selective chemokine binding receptor. Infect Disord Drug Targets 9:548-56
Streblow, D N; Dumortier, J; Moses, A V et al. (2008) Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Curr Top Microbiol Immunol 325:397-415
Dumortier, Jerome; Streblow, Daniel N; Moses, Ashlee V et al. (2008) Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J Virol 82:6524-35
Streblow, Daniel N; Orloff, Susan L; Nelson, Jay A (2007) Acceleration of allograft failure by cytomegalovirus. Curr Opin Immunol 19:577-82
Streblow, Daniel N; van Cleef, Koen W R; Kreklywich, Craig N et al. (2007) Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. J Virol 81:3816-26
Melnychuk, Ryan M; Smith, Patsy; Kreklywich, Craig N et al. (2005) Mouse cytomegalovirus M33 is necessary and sufficient in virus-induced vascular smooth muscle cell migration. J Virol 79:10788-95

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