Novel mechanisms of age-enhanced vasculopathy after heart transplantation

心脏移植后年龄加重血管病变的新机制

• 批准号: 10088381
• 负责人: Daniel Robert Goldstein
• 金额: $ 54.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088381
• 关键词: Adaptor Signaling Protein; Address; Age; Age-Years; Aging; Allografting; Atherosclerosis; Autophagocytosis; CCL2 gene; Cells; Chronic; Clinical Research; Complement; Data; Development; Disabled Persons; Donor person; Effectiveness; Exhibits; Genes; Heart; Heart Transplantation; Heart failure; Hyperlipidemia; Immune; Immune signaling; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Lead; Link; Methods; Mitochondria; Mus; Organ Transplantation; Pathway interactions; Patients; Publishing; Reporter; Risk Factors; Role; Sirolimus; Smooth Muscle Myocytes; Testing; Therapeutic; Toll-like receptors; Transplantation; Vascular Diseases; Vascular Smooth Muscle; Work; age effect; aged; allotransplant; atherogenesis; cell age; insight; monocyte; mortality; novel; novel strategies; novel therapeutics; osteopontin; parkin gene/protein; recruit; transplant model; vascular inflammation

Project Summary Heart transplantation is a vital therapy for end-stage heart failure. The effectiveness of this therapy, however, is largely limited by the shortage of donors. Regrettably, less than 40% of available heart donations are used for transplantation and the rate of use is declining due to increasing donor age. Transplants from donors older than 55 years of age are typically disregarded as increasing donor age is the strongest independent factor for both mortality and the development of chronic allograft vasculopathy (CAV), the leading cause of graft loss for organ transplants. Additionally, older donor hearts often exhibit atherosclerosis, rendering them unsuitable for transplantation. However, the mechanisms by which donor age increases CAV remain unknown. Our prior work demonstrates that aged murine vascular smooth muscle cells (VSMC) contribute to vascular inflammation by producing IL-6, CCL2 and osteopontin via MyD88, an innate immune adaptor protein downstream of the Toll like receptors. Our preliminary data also indicate that aging impairs mitophagy, i.e., the clearance of damaged mitochondria, within VSMC to enhance vascular inflammation. We therefore hypothesize that impaired mitophagy within aged donor VSMC leads to MyD88-dependent vascular inflammation that enhances CAV. To test this hypothesis, we will use novel mice in which MyD88 is selectively deleted within VSMC to examine whether MyD88 expression within VSMC of the aged donor vasculature is critical for CAV in a murine heart transplant model (Aim 1). We will also examine whether MyD88 expression within VSMC of the aged donor vasculature is critical for the progression of pre-existing donor atherosclerosis after cardiac transplantation by employing a novel method to induce atherosclerosis in the donor heart prior to transplantation. In addition, we will use young mice in which either autophagy or mitophagy is disabled within VSMC, to determine if autophagy or mitophagy in these cells controls CAV (Aim 2). We will complement this approach by examining if administration of agents that enhance autophagy, e.g., rapamycin or mitophagy e.g., actinonin, to aged donor mice reduces CAV after cardiac transplantation. We expect that our study will directly link inflammatory pathways in the donor vasculature to CAV. Our results could lead to new therapeutics to reduce both the development of CAV and the progression of native vessel atherosclerosis in donor hearts. Such therapeutics could tremendously increase the pool of heart transplant donors and save lives of patients with end stage heart failure.

项目摘要 心脏移植是最终心力衰竭的重要疗法。但是，这种疗法的有效性 在很大程度上受捐助者的短缺限制。遗憾的是，不到40％的可用心脏捐赠 由于供体年龄的增加，用于移植和使用率正在下降。捐助者年龄较大的移植物 由于捐助者年龄的增加是最强的独立因素，通常会忽略55岁以上的年龄 死亡率和慢性同种异体血管病（CAV）的发展，这是移植物损失的主要原因 器官移植。此外，年长的供体心经常表现出动脉粥样硬化，使它们不适合 移植。但是，供体年龄增加CAV的机制仍然未知。我们的先验 工作表明，老化的鼠血管平滑肌细胞（VSMC）有助于血管炎症 通过通过MyD88产生IL-6，CCL2和骨桥蛋白，这是一种先天的免疫适配器蛋白 像受体一样收费。我们的初步数据还表明，衰老会损害线粒体，即清除 VSMC内部损坏的线粒体可增强血管炎症。因此，我们假设 老年供体VSMC内的线索受损会导致MyD88依赖性血管炎症，从而增强 骑士。为了检验这一假设，我们将使用新的小鼠，其中MyD88在VSMC中有选择地删除到 检查老年供体脉管系统VSMC中MyD88的表达是否对于鼠中的CAV至关重要 心脏移植模型（AIM 1）。我们还将检查MyD88在老年人的VSMC中是否表达 供体脉管系统对于心脏后现有的供体动脉粥样硬化的进展至关重要 通过采用一种新的方法来移植，在供体心脏中诱导动脉粥样硬化 移植。此外，我们将使用年轻的老鼠，其中自噬或线粒体被禁用 VSMC，确定这些细胞中的自噬或线粒体是否控制CAV（AIM 2）。我们将补充这个 通过检查是否可以增强自噬的药物的给药，例如雷帕霉素或线粒体，例如 阳式素，向老年供体小鼠减少心脏移植后CAV。我们希望我们的研究将直接 将供体脉管系统中的炎症途径与CAV联系起来。我们的结果可能会导致新的治疗方法 减少供体心脏中天然血管性动脉粥样硬化的CAV的发展和进展。 这种治疗药可以极大地增加心脏移植供体的池并挽救患者的生命 终结舞台心力衰竭。