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: 7581712
• 负责人: SUSAN L ORLOFF
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581712
• 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血管疾病发展中的作用，例如动脉粥样硬化，再狭窄和移植血管硬化症（TVS）。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，以及从血管培养基到内膜的迁移，最终导致血管缩小。临床研究已直接将人类巨细胞病毒（HCMV）与血管成形术后电视和血管再狭窄的加速以及动脉粥样硬化相关。但是，HCMV参与血管疾病加速的机制尚不清楚。为了解决这个问题，我们开发了一种老鼠心脏移植模型，该模型展现了人类电视开发的所有标志。我们小组和其他人的研究表明，大鼠CMV（RCMV）感染显着加速了TV的发展以及大鼠心脏同种异体移植模型中的慢性排斥。我们还表明，HCMV和RCMV都可以诱导由病毒编码的趋化因子受体US 28或R33介导的SMC迁移。最近，我们证明，R33的插入缺失显着增加了慢性排斥的时间，并减慢了大鼠心脏移植模型中电视过程的动力学，这表明该病毒趋化因子受体在血管疾病的RCMV加速中起重要作用。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，使用SMC迁移的体外模型，我们将定义结合R33，其信号通路的趋化因子，以及它们诱导SMC迁移的能力。我们还将确定与配体结合和信号传导有关的R33的临界氨基酸。然后，我们将通过研究R33配体结合和信号传导与TVS加速的关系的关系，将这些研究扩展到体内大鼠心脏同种异体移植模型，通过研究对TVS在配体结合和信号传导中适当的R33突变的影响。 公共卫生相关性：60-90％的捐助者和接受者人口受到CMV的影响，这使CMV感染对电视的开发产生了主要关注。因此，为了避免需要再移植并延长移植物的生存，我们必须了解电视的致病机制，更具体地说，是该过程的CMV相关机制。旨在减少电视的新型治疗剂的开发将使所有移植受者受益。