Cytomegalovirus Chemokine Receptors in Transplant Vascular Sclerosis

描述（由申请人提供）：本项目的长期目标是确定病毒病原体在血管疾病（如动脉粥样硬化、再狭窄和移植血管硬化（TVS））发展中的作用。所有这些疾病都是机械或免疫介导的损伤的结果，随后是炎症和随后的平滑肌细胞（SMC）增殖和从血管中膜迁移到内膜，最终导致血管狭窄。临床研究表明，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直接相关。然而，HCMV加速血管疾病的机制尚不清楚。为了解决这个问题，我们开发了一种大鼠心脏移植模型，该模型显示了人类TVS发展的所有标志。本课题组和其他研究表明，大鼠巨细胞病毒（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，分别由病毒编码的趋化因子受体US 28或R33介导。最近，我们已经证明，R33的插入缺失显着增加了慢性排斥反应的时间，并减缓了大鼠心脏移植模型中TVS过程的动力学，这表明这种病毒趋化因子受体在RCMV加速血管疾病中发挥着重要作用。因此，这项建议的一部分将继续我们的检查，这种病毒趋化因子受体在疾病的发展。此外，使用SMC迁移的体外模型，我们将定义结合R33的趋化因子，它们的信号通路，以及它们诱导SMC迁移的能力。我们还将确定参与配体结合和信号传导的R33的关键氨基酸。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配体结合和信号转导与TVS加速的关系，通过研究在配体结合和信号转导中具有适当R33突变对TVS发展的影响。 公共卫生相关性：60-90%的供体和受体群体潜伏感染CMV，使得CMV感染对TVS发展的影响成为主要关注点。因此，为了避免再次移植的需要，并延长移植物存活，我们必须了解TVS的致病机制，更具体地说，CMV相关的机制，这一过程。开发旨在减少TVS的新疗法将使所有移植受者受益。

DESCRIPTION (provided by applicant): 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 signaling 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. PUBLIC HEALTH RELEVANCE: Between 60-90% of the donor and recipient population are latently infected with CMV making the effect of CMV infection on the development of TVS a major concern. Therefore, to avoid the need for retransplantation, and to prolong graft survival, we must understand the pathogenic mechanisms of TVS, and more specifically, the CMV-associated mechanisms of this process. The development of novel therapeutics designed to reduce TVS would benefit all transplant recipients.