Cytomegalovirus Chemokine Receptors in Transplant Vascular Sclerosis

移植血管硬化中的巨细胞病毒趋化因子受体

• 批准号: 7842075
• 负责人: SUSAN L ORLOFF
• 金额: $ 32.68万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842075
• 关键词: Acceleration; Address; Allografting; Amino Acids; Angioplasty; Atherosclerosis; Binding; Binding Sites; Blood Vessels; Cell Proliferation; Cells; Characteristics; Chronic; Clinical Research; Cytomegalovirus; Development; Disease; Exhibits; Goals; Graft Survival; Heart; Heart Transplantation; Human; Immune; In Vitro; Infection; Inflammation; Injury; Kinetics; Lesion; Ligand Binding; Mechanics; Mediating; Modeling; Mutation; Play; Population; Process; Rattus; Role; Sclerosis; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Time; Transplant Recipients; Transplantation; Vascular Diseases; Viral; Virus; allotransplant; cell motility; cell type; chemokine; chemokine receptor; design; heart allograft; in vitro Model; in vivo; migration; mutant; novel therapeutics; pathogen; public health relevance; restenosis; retransplantation

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.

描述（由申请人提供）：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（TVS）等血管疾病发展中的作用。所有这些疾病都是机械或免疫介导损伤的结果，随后发生炎症和随后的平滑肌细胞（SMC）增殖并从血管中膜迁移到内膜，最终导致血管狭窄。临床研究表明，人巨细胞病毒 (HCMV) 与 TVS 加速、血管成形术后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，该模型表现出人类 TVS 发展的所有特征。我们小组和其他人的研究表明，大鼠 CMV (RCMV) 感染显着加速 TVS 的发展以及大鼠心脏同种异体移植模型中的慢性排斥反应。我们还表明，HCMV 和 RCMV 均可诱导 SMC 迁移，该迁移分别由病毒编码的趋化因子受体 US 28 或 R33 介导。最近我们证明，R33 的插入缺失显着增加了慢性排斥反应的时间，并减慢了大鼠心脏移植模型中 TVS 过程的动力学，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，该提案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，利用 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 中参与配体结合和信号传导的关键氨基酸。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，通过研究配体结合和信号传导中适当的 R33 突变对 TVS 发育的影响，进一步表征 R33 配体结合和信号传导与 TVS 加速的关系。 公共卫生相关性：60-90% 的供体和受者人群均潜伏感染 CMV，这使得 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，了解该过程中与 CMV 相关的机制。旨在减少 TVS 的新型疗法的开发将使所有移植受者受益。