Cytomegalovirus Chemokine Receptors in Transplant Vascular Sclerosis

项目摘要： 该项目的长期目标是确定病毒病原体在血管内皮细胞发育中的作用。 疾病如动脉粥样硬化、再狭窄和移植血管硬化（TVS）。所有这些疾病 是机械或免疫介导的损伤，随后是炎症和随后的炎症反应的结果。 平滑肌细胞（SMC）增殖并从血管中膜迁移到内膜，最终导致 血管狭窄临床研究已将人巨细胞病毒（HCMV）与 血管成形术后TVS加速和血管再狭窄以及动脉粥样硬化。但 HCMV加速血管疾病的机制尚不清楚。解决这一问题 我们已经开发了一种大鼠心脏移植模型，该模型显示了TVS发展的所有特征， 人类我们小组和其他人的研究表明，大鼠CMV（RCMV）感染显著加速 大鼠心脏移植模型中TVS的发展以及慢性排斥反应。我们还 表明HCMV和RCMV都可以诱导SMC迁移，这是由病毒编码的趋化因子介导的， 受体US 28或R33。最近，我们已经证明，R33的插入缺失， 显著增加慢性排斥反应的时间，并减慢大鼠TVS过程的动力学 心脏移植模型表明这种病毒趋化因子受体在RCMV中起重要作用 加速血管疾病。因此，本建议的一部分将继续我们对这种病毒的研究， 趋化因子受体在疾病发展过程中的作用。此外，使用SMC迁移的体外模型， 我们将定义与R33结合的趋化因子，它们的信号传导途径，以及它们诱导SMC的能力。 迁移我们还将确定参与配体结合的R33的关键氨基酸， 信号然后，我们将这些研究扩展到体内大鼠心脏同种异体移植模型，以进一步表征 R33配体结合和信号传导与TVS加速的关系，通过研究对 开发在配体结合和信号传导中具有适当R33突变的TVS。

Project Summary: 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. 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. To address this issue we have developed a rat heart transplant model that exhibits all of the hallmarks of the development of TVS in humans. Studies by our group and others have shown that rat CMV (RCMV) infection significantly accelerates both the development of TVS as well as chronic rejection in the rat heart allotransplant model. We have also shown that both HCMV and RCMV can induce SMC migration that is mediated by virally encoded chemokine receptors US 28 or R33, respectively. Recently we have demonstrated that the insertional deletion of R33 significantly increases the time to chronic rejection, and slows the kinetics of the process of TVS in the rat heart transplant model suggesting that this viral chemokine receptor plays an important role in RCMV acceleration of vascular disease. Accordingly, part of this proposal will continue our examination of this viral chemokine receptor during the development of disease. In addition, using an in vitro model of SMC migration, we will define the chemokines that bind R33, their siginaling pathways, as well as their ability to induce SMC migration. We will also determine the critical amino acids of R33 that are involved in ligand binding and signaling. We will then extend these studies to the in vivo rat heart allotransplant model to further characterize the relationship of R33 ligand binding and signaling to TVS acceleration by studying the effects on the development of TVS with appropriate R33 mutations in ligand binding and signaling.