This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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-mediated injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and migration from the vessel media to the intima, which culminates in vessel narrowing. Besides SMC, the other key cells in this process are monocyte-derived macrophages (MDM) and endothelial cells. 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. Studies by our group and others have shown that CMV can accelerate atherosclerosis in mouse models. 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. Chemokine receptors are known to play an important role in the development of vasculopathies and we hypothesize that the CMV chemokine receptors are integral in the acceleration of this disease process. 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 US28 homologue. 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. The MCMV heart transplant model offers a unique system to quantitatively assess the mechanisms of virus-accelerated vasculopathy using both viral and mouse genetics. Therefore, in this project we will use the in vitro and in vivo systems that we have established over the previous funding period to elucidate the role of CMV chemokine receptors in virus accelerated vasculopathy.
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