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.

我们已经报道了对胶原蛋白α 1 (V) [col(V)]自身免疫在急性和慢性中的主要作用