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: 8208103
• 负责人: SUSAN L ORLOFF
• 金额: $ 38.12万
• 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/8208103
• 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; Pathway interactions; 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; restenosis; retransplantation

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.

项目摘要： 该项目的长期目标是确定病毒病原体在血管发展中的作用 诸如动​​脉粥样硬化，再狭窄和移植血管硬化症（TVS）之类的疾病。所有这些疾病 是机械或免疫介导的损伤的结果，随后发炎，随后 平滑肌细胞（SMC）增殖和从血管培养基到内膜的迁移 船只变窄。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。但是， HCMV参与血管疾病加速的机制尚不清楚。解决这个问题 我们已经开发了一种老鼠心脏移植模型，该模型展现了电视开发的所有标志 人类。我们小组和其他人的研究表明，大鼠CMV（RCMV）感染显着加速了 在大鼠心脏同种异体移植模型中，电视的发展以及慢性排斥。我们也有 表明HCMV和RCMV均可诱导由病毒编码趋化因子介导的SMC迁移 受体我们分别28或R33。最近，我们证明了R33的插入删除 大大增加了慢性排斥的时间，并减慢了大鼠电视过程的动力学 心脏移植模型表明该病毒趋化因子受体在RCMV中起重要作用 血管疾病的加速。因此，该提案的一部分将继续我们对这种病毒的检查 疾病发展过程中的趋化因子受体。另外，使用SMC迁移的体外模型 我们将定义结合R33，其偏向途径的趋化因子，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的临界氨基酸和 信号。然后，我们将将这些研究扩展到体内大鼠心脏同倍移植模型，以进一步表征 R33配体结合和信号传导与电视加速的关系，通过研究对 在配体结合和信号传导中具有适当R33突变的电视开发。