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, which culminates in vessel narrowing. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of TVS and restenosis as well as atherosclerosis. However, the mechanism(s) involved in the acceleration of vascular disease by HCMV is unknown. Studies by our group and others have implicated endothelial cells (EC), macrophages (MDM) and SMC as potential reservoirs of the virus in the host. Unfortunately, an animal model for HCMV is unavailable. However, mouse cytomegalovirus (MCMV) provides an ideal system to study mechanisms of pathogenesis and cellular tropism in the mouse model. Recently, we have developed a mouse heart transplantation model of TVS, which exhibits all of the hallmarks of human disease. We have also shown that CMV accelerates the progression and severity of TVS. Therefore, in this project we will utilize the mouse TVS model in combination with MCMV to assess the role of viral infection of MDM and EC on the acceleration of disease. In the first specific aim, we will utilize MCMV EC and MDM tropic mutants, which inhibit growth of virus in these cell types to assess the contribution of viral infection of these cells in the acceleration of TVS. In the second specific aim, we will utilize mice which specifically express Cre recombinase in EC and MDM in combination with recombinant MCMV that contain Lox sites which inactivate the virus in the presence of Cre enzyme to assess the role of MCMV replication in MDM and EC in the acceleration of TVS. In the last specific aim, we will examine viral mechanisms which accelerate TVS through ablation of MCMV genes which mediate inflammatory events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071695-04
Application #
6945773
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Tolunay, Eser
Project Start
2002-09-30
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$377,500
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
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
Streblow, Daniel N; Kreklywich, Craig N; Smith, Patricia et al. (2005) Rat cytomegalovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33. Am J Transplant 5:436-42
Melnychuk, Ryan M; Streblow, Daniel N; Smith, Patricia P et al. (2004) Human cytomegalovirus-encoded G protein-coupled receptor US28 mediates smooth muscle cell migration through Galpha12. J Virol 78:8382-91

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