IMMUNOPATHOLOGY OF RENAL DISEASE IN MAN

人类肾病的免疫病理学

• 批准号: 2137430
• 负责人: CURTIS B WILSON
• 金额: $ 30.95万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-04-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2137430
• 关键词: Goodpasture's syndrome; antigens; basement membrane; cellular immunity; cytokine; disease /disorder model; endopeptidases; enzyme inhibitors; extracellular matrix; fibronectins; genetically modified animals; glomerulonephritis; human tissue; immune complex diseases; immunomodulators; immunopathology; inflammation; interleukin 1; laboratory mouse; laboratory rat; platelet derived growth factor; renal failure

Human glomerulonephritis (GN) and its glomerulosclerotic (GS) sequela are a major cause of renal failure necessitating expensive dialysis and transplantation therapy. Better understanding of the immune pathogenesis and therapeutic manipulation of the underlying molecular mechanisms of sclerosis would stall buildup of extracellular matrix (ECM) and loss of nephron units in GS. Two areas of this problem will be studied from a molecular perspective: 1) the reactive epitopes/V-gene interactions and possible abnormalities of alpha3 (IV) collagen chains in anti-glomerular basement membrane (GBN) antibody (Ab) GN and Alport syndrome as well as assessment of protein-protein interactions with the alpha-chains; 2) the role of ECM proteinases and their inhibitors in excess accumulation of ECM in GS. The genomic DNA for the carboxyl terminal NCI domain of alpha3(lV) collagen, a major anti-GBM Ab Ag, was cloned with evidence of alternatively spliced mRNAs which vary relative to one another during kidney development. The carboxyl terminal variations predicted by the alternatively spliced mRNAs may be control mechanisms and could help to explain Ag variations among patients as well as structural abnormalities in GBM of patients with Alport syndrome in whom alpha3 (IV) Ag may be missing. A combination of synthetic peptides, biochemical fractions, and expressed recombinant fragments, including unique deduced peptides from the spliced mRNAs of alpha3(IV) and their reactive Abs, will help define anti-GBM Ab epitopes and their variations in normal and Alport GBM. The epitope knowledge will be related to the V-gene composition of the autoantibody as an avenue to immunospecific treatment. Inhibitors (PAI 1, TIMPs) of ECM proteinases may impair ECM degradation during sclerosis. The role of the proteinases (u-PA, transin) and their inhibitors, as well as often associated coagulation proteins, will be sought in manipulative experimental studies (including mice transgenic for PAI 1 and transin) and in immunocytochemical and molecular studies in human renal biopsies. These studies will document molecular and enzymatic abnormalities in GN and GS and set the stage for evaluation of molecular therapy.

人肾小球肾炎（GN）及其肾小球硬化（GS）续集是 肾衰竭的主要原因需要昂贵的透析和 移植疗法。 更好地了解免疫发病机理 以及对基本分子机制的治疗操纵 硬化症会停滞细胞外基质（ECM）和丢失 GS中的肾单位单位。该问题的两个领域将从 分子透视：1）反应性表位/V基因相互作用和 抗斜体中α3（IV）胶原蛋白链的可能异常 地下膜（GBN）抗体（AB）GN和Alport综合征以及 评估蛋白质 - 蛋白质与α-链的相互作用； 2） ECM蛋白酶及其抑制剂在ECM过多积累中的作用 在GS中。 α3（LV）的羧基NCI结构域的基因组DNA（LV） 胶原蛋白是一种主要的抗GBM AB AG，被克隆了 或者，在剪接的mRNA中相对于彼此而异 肾脏发展。 由 或者，剪接的mRNA可能是控制机制，可能有助于 解释患者之间的AG变化以及结构异常 在ALPHA3（IV）Ag的Alport综合征患者的GBM中 丢失的。 合成肽，生化部分和 表达的重组片段，包括来自独特的推导肽 Alpha3（IV）的剪接mRNA及其反应性ABS将有助于定义 抗GBM AB表位及其在正常和Alport GBM中的变化。 这 表位知识将与V-Gene组成有关 自身抗体是免疫特异性治疗的途径。 抑制剂（PAI 1， ECM蛋白酶的TIMPS）可能会损害硬化过程中ECM降解。 蛋白酶（U-PA，透蛋白）及其抑制剂的作用 经常相关的凝血蛋白，会在操纵中寻求 实验研究（包括PAI 1和Transin的小鼠转基因）和 在人类肾脏活检中的免疫细胞化学和分子研究中。 这些研究将记录GN的分子和酶促异常 和GS并为评估分子疗法奠定了基础。