RESPONSE OF RENAL CELLS IN INTERSTITIAL NEPHRITIS

间质性肾炎中肾细胞的反应

• 批准号: 2145463
• 负责人: ERIC Grant NEILSON
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2145463
• 关键词: DNA footprinting; angiotensin II; antisense nucleic acid; autoimmune disorder; basement membrane; chimeric proteins; collagen; epithelium; fibroblasts; gene expression; histocompatibility gene; inflammation; interstitial nephritis; kidney cell; kidney hypertrophy; laboratory mouse; membrane reconstitution /synthesis; molecular cloning; radioimmunoassay; renal tubule; reporter genes; transfection

DESCRIPTION (Adapted from investigator's abstract): The appearance of interstitial nephritis is an expected development in the natural history of all forms of progressive renal failure. The investigators have been studying this inflammatory process using an experimental model of immune-mediated interstitial nephritis in mice called anti-tubular basement membrane (alphaTBM) disease. Primary immune injury is produced in this model by T cells and antibodies (alphaTMB-Ab/alpha3M-1-Ab) which are directed at a tubular target antigen (3M-1) expressed by proximal tubular epithelium. Histologic damage occurs through the formation of interstitial mononuclear cell infiltrates that subsequently invoke a progressive fibrogenesis with tubular atrophy. The emergence of this autoimmune process rendering structural damage is a product of complex biochemical events that depend on two interactive components; one component is the development of a destructive nephritogenic immune response. The other component is the reaction of the tubulo- interstitium to mononuclear intrusion. The long term purpose and goals of this application have been focused on the latter issue. In their current renewal they have concentrated selectively on several fundamental, inflammation-relevant protein systems which modulate the immunologic visibility, tissue boundaries, cell size, and phenotype of target tubular epithelium and their associated fibroblasts. Over the course of the last few years their work can be distilled down and tracked into four critical areas: one area has been to determine how MHC class II genes are regulated in tubular epithelium; the second area has been to determine how type IV collagen genes are modulated during basement membrane remodelling; the third area has been to understand the molecular mechanisms of tubular hypertrophy and how cellular enlargement may influence the expression of nephritogenic antigens; and the fourth area has been to develop antibodies and molecular probes which can be used specifically to identify tubulo-interstitial fibroblasts. These four project themes collectively bridge the disciplines of genetics and biochemistry with basic pathophysiology in order to better discern major processes leading to aberrant structural change in interstitial tissue. The investigators' experiments rely on both in vitro and in vivo technologies in order to assemble a comprehensive database on this subject; these technologies include the use of cell culture, radioimmunoassay, cDNA cloning, chimeric reporter gene constructs, gel retardation assays, DNA footprinting, transgene replacement, eurkaryotic transfection, and antisense inhibition. They believe their approach and the level of their analysis will lead to a better comprehension of critical somatic cell responses to immune events that may offer new insights regarding the formation of rational strategies for improved treatment of interstitial injury.

描述（改编自研究者摘要）： 间质性肾炎是自然病程中的一种预期发展 各种形式的进行性肾衰竭 调查人员一直在 研究这种炎症过程的实验模型， 免疫介导的小鼠间质性肾炎称为抗肾小管 基底膜（alphaTBM）疾病。 产生原发性免疫损伤 在该模型中，通过T细胞和抗体（α TMB-Ab/α 3 M-1-Ab）， 针对由近端表达的肾小管靶抗原（3 M-1）， 肾小管上皮 组织学损伤是通过形成 间质单核细胞浸润，随后引起 进行性纤维化伴肾小管萎缩。 出现这种 自身免疫过程导致结构损伤是一种复杂的 生物化学事件取决于两个相互作用的成分;一个 组成部分是一种破坏性的致肾炎免疫的发展 反应 另一个成分是微管的反应- 氚到单核侵入。 长期目的和目标 本申请的重点是后一个问题。 在目前的更新中，他们有选择地集中在几个方面， 基本的，炎症相关的蛋白质系统，调节 免疫可见性、组织边界、细胞大小和表型 靶向肾小管上皮及其相关的成纤维细胞。 来 在过去几年中，他们的工作可以提炼出来， 跟踪到四个关键领域：一个领域是确定如何 MHCII类基因在肾小管上皮中受到调节;第二个区域 已经确定了IV型胶原基因是如何被调节的， 基底膜重塑;第三个领域是了解 肾小管肥大的分子机制以及细胞如何增大 可能影响致肾炎抗原的表达;第四， 该领域一直致力于开发抗体和分子探针， 专门用于鉴定肾小管间质成纤维细胞。 这些 四个项目主题共同连接了遗传学和 生物化学与基础病理生理学，以便更好地辨别主要 导致间质组织异常结构变化的过程。 研究人员的实验依赖于体外和体内 技术，以组装一个全面的数据库， 主题;这些技术包括使用细胞培养， 放射免疫分析，cDNA克隆，嵌合报告基因，凝胶 阻滞试验，DNA足迹法，转基因替代，欧洲 转染和反义抑制。 他们相信他们的方法， 他们的分析水平将导致更好地理解 体细胞对免疫事件的关键反应可能提供新的 关于形成合理战略的见解， 间质损伤的治疗。