Cytomegalovirus Chemokine Receptors in Transplant Vascular Sclerosis

描述(申请人提供)：该项目的长期目标是确定病毒病原体在动脉粥样硬化、再狭窄和移植血管硬化症(TVS)等血管疾病发展中的作用。所有这些疾病都是机械性或免疫介导性损伤的结果，随后是炎症和随后的平滑肌细胞(SMC)增殖和从血管中层向内膜迁移，最终导致血管狭窄。临床研究表明，人巨细胞病毒(HCMV)与TVS的加速、血管成形术后的血管再狭窄以及动脉粥样硬化直接相关。然而，人巨细胞病毒加速血管病变的机制(S)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，该模型显示了电视在人类身上发展的所有特征。我们等人的研究表明，在大鼠心脏移植模型中，大鼠巨细胞病毒(RCMV)感染显著加速了TVS的发展和慢性排斥反应。我们还表明，HCMV和RCMV都可以诱导SMC迁移，这种迁移分别由病毒编码的趋化因子受体US 28或R33介导。最近，我们在大鼠心脏移植模型中发现，R33基因的插入缺失显著延长了慢性排斥反应发生的时间，并减缓了TVS过程的动力学过程，表明这种病毒趋化因子受体在血管疾病的RCMV加速中起着重要作用。因此，这项建议的一部分将继续我们在疾病发展过程中对这种病毒趋化因子受体的检查。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R33参与配体结合和信号转导的关键氨基酸。然后，我们将把这些研究扩展到在体大鼠心脏移植模型，通过研究R33配体结合和信号突变对TVS发育的影响，进一步表征R33配体结合和信号与TVS加速的关系。 公共卫生相关性：60%-90%的捐赠者和接受者人群潜伏着感染CMV，这使得CMV感染对电视节目发展的影响成为一个主要关注的问题。因此，为了避免再次移植的需要，延长移植物的存活时间，我们必须了解TVS的致病机制，更具体地说，这一过程中的CMV相关机制。旨在减少电视转移率的新疗法的开发将使所有移植接受者受益。

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.