Roles of Activated Collagen V Stroma in Translant Rejection and Arteriopathies

活化的 V 型胶原基质在移植排斥和动脉病中的作用

• 批准号: 7810359
• 负责人: DANIEL S GREENSPAN
• 金额: $ 35.69万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810359
• 关键词: Acute; Address; Adherence; Adoptive Transfer; Adult; Affect; Affinity; Antibodies; Apolipoprotein E; Apoptosis; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Autoimmune Process; Autoimmune Responses; Autoimmunity; Back; Behavior; Binding; Biological Models; Bronchiolitis; Cells; Cellular Immunity; Choristoma; Chronic; Collagen; Collagen Receptors; Coronary artery; Data; Deposition; Differential Threshold; Doxycycline; Epithelial Cells; Epithelium; Epitopes; Extracellular Matrix; Feedback; Fibrillar Collagen; Fractionation; Genes; Graft Rejection; Growth; Heart Transplantation; Heart-Lung Transplantation; Human; Immune; Immune Sera; In Vitro; Inflammatory; Injury; Knock-in Mouse; Knock-out; Knockout Mice; Lesion; Link; Lung; Molecular; Mus; Mutation; Nature; Organ Transplantation; Pathogenesis; Pathologic Processes; Pathology; Peptides; Proteins; RNA; Rattus; Relative (related person); Reporting; Rodent; Role; Series; Smooth Muscle Myocytes; Sodium Chloride; Staining method; Stains; Structure; T-Lymphocyte; Technology; Testing; Tissues; Transgenes; Transplantation; Vascular Diseases; Work; allograft rejection; base; cell type; cytokine; heart allograft; homologous recombination; human disease; improved; in vivo; insight; lung allograft; migration; mouse model; novel; promoter; research study

We've reported major roles for autoimmunity to the alpha 1 (V) of collagen V [col(V)] in acute and chronic lung transplant rejection. Data from these studies led us to hypothesize that abnormal homotrimers of alpha 1(V) chains induce anti-col(V) autoimmunity and organ transplant rejecfion. To test the hypothesis, we invesfigated whether the autoimmune component of atherosclerosis involves anfi-col(V) autoimmunity, based solely on the fact that alpha 1 (V) homotrimers are found in human atherosclerotic plaques. Here we demonstrate that atherosclerosis in humans and rodents is in fact associated with anfi-col(V) autoimmunity, constituting an important proof-of-concept in support ofthe link between alpha 1(V) homotrimer formafion and anti-col(V) autoimmunity. We propose studies to demonstrate that aberrent alpha 1(V) homotrimers are expressed in obliterative bronchiolitis (OB), which underiies chronic lung transplant rejection; and in cardiac allograft vasculopathy (CAV), an atherosclerosis-like rejection pathology in heart transplants. We will also use homologous recombinafion to condifionally induce expression of alpha 1(V) homotrimers in vivo in mouse adult lung epithelium, adult smooth muscle cells, and in ali adult tissues that normally express col(V) to directly test the roles of this aberrant form of col(V) in OB and CAV, upon lung and heart transplantation, respectively; and in atherosclerosis, upon crossing of alpha 1 (V) homotrimer-expressing mice with ApoE-null mice. Various types of immune challenges and adoptive transfers will further test the roles of alpha 1 (V) homotrimers in initiating anti-col(V) autoimmunity in these novel mouse model systems. We will also employ homologous recombination to generate mice in which alpha 1 (V) epitopes, found by peptide analysis to be the most recognized by anti-col(V) reactive T cells and antibodies, are removed from the alpha 1(V) gene in vivo, to test the true roles of such epitopes in OB, CAV, atherosclerosis and anti-col(V) autoimmunity. Finally, we propose a series of in vitro and in vivo experiments to test the concept of an "activated" alpha 1(V)- containing stroma that can enhance and perpetuate pathological states, including OB, CAV, atherosclerosis, and perhaps other pathologies as well, and how such a stroma affects cellular behaviors.

我们已经报道了对V型胶原的α1(V)的自身免疫在急慢性疾病中的主要作用 肺移植排斥反应。来自这些研究的数据使我们假设，阿尔法的异常同源三聚体 1(V)链诱导抗胶(V)自身免疫和器官移植排斥反应。为了检验这一假设，我们 研究动脉粥样硬化的自身免疫成分是否涉及ANFI-ol(V)自身免疫， 仅基于在人类动脉粥样硬化斑块中发现α1(V)同源三聚体这一事实。在这里我们 证明人类和啮齿动物的动脉粥样硬化实际上与ANFI-ol(V)自身免疫有关， 构成支持α1(V)同源三聚体之间联系的重要概念验证 和抗胶原(V)自身免疫。我们提出的研究表明，异常的α1(V)同源三聚体是 在导致慢性肺移植排斥反应的闭塞性毛细支气管炎(OB)中表达；在心脏 同种异体血管病(CAV)，心脏移植中的一种动脉粥样硬化样排斥反应病理。我们还将 用同源重组蛋白在小鼠体内条件性诱导表达α1(V)同源三聚体 小鼠成体肺上皮、成体平滑肌细胞和ALI成体组织中正常表达COL(V)的细胞 为了直接测试这种变异形式的COL(V)在OB和CAV中在肺和心脏移植中的作用， 在动脉粥样硬化中，当表达α1(V)同源三聚体的小鼠与载脂蛋白E缺失的小鼠杂交时 老鼠。各种类型的免疫挑战和过继转移将进一步考验阿尔法1(V)的作用。 在这些新的小鼠模型系统中启动抗胶(V)自身免疫的同源三聚体。我们还将利用同源重组来产生小鼠，在小鼠中，通过肽分析发现最能被抗胶(V)反应性T细胞和抗体识别的阿尔法1(V)表位从体内的阿尔法1(V)基因中移除，以测试这些表位在OB、CAV、动脉粥样硬化和抗胶(V)自身免疫中的真实作用。最后，我们提出了一系列的体外和体内实验，以测试“激活的”阿尔法1(V)的概念- 含有可以增强和保持病理状态的间质，包括OB、CAV、动脉粥样硬化，也许还有其他病理，以及这样的间质如何影响细胞行为。