BIOLOGY OF PROGRESSIVE NEPHRON DESTRUCTION

许多肾脏疾病的特点是病情不断恶化。 到终末期肾功能衰竭。有时，这个过程就是 启动事件的持续活动的结果。在许多 例如，导致肾小球破坏的途径不佳 了解各种机制。可能的机制包括肾小球 高滤过与高血压、肾小球系膜积聚 血清衍生大分子与肾小球内激活 凝结。这些可能的机制究竟是如何导致 观察到的功能和结构恶化尚不清楚。它 然而，人们普遍认为，一些有效的生物学 分子参与了这些过程。这些分子包括 脂源性介质，如环氧合酶和脂氧合酶 花生四烯酸代谢产物、血小板活化因子、表皮 生长因子(EGF)、血小板衍生生长因子(PDGF)、 转化生长因子β(TGF-B)、血管紧张素II和 白介素1。该中心助学金利用并行技术在 生理学、病理学、药理学、生物化学、细胞生物学、 和分子生物学来定义导致 肾小球和肾小管功能障碍与进行性肾小球 毁灭。多种实验技术被应用于 代表两个一般类别的特定疾病模型：非 免疫学包括肾肿块消融术，嘌呤霉素- 氨基核苷肾病与阿霉素中毒 免疫学，即肾移植排斥反应。标准 肾小球微穿刺术，以及新开发的 系列性肾小球微穿刺术允许 疾病过程在不同时间的功能特征 间隔时间。肾小球损伤的形态定量将是 与肾小球功能的测量结果相关。离体 肾小球标本及培养的检查 肾小球细胞类型将阐明其重要作用 生物介体在生产功能和结构中的作用 改变。硬化肾小球的基质成分将是 基质合成的信使核糖核酸的定义和调控 通过原位杂交技术进行评估。这个角色是 重要的生物学介质在改变上皮细胞中的作用 还将利用体外小管检查功能。 灌流。本节目中的调查人员代表了一种独特的 融合了学科和复杂的技术，可以 聚焦于肾脏疾病中最优先的问题之一， 即导致进展性肾单位的发病机制 毁灭。

Many kidney diseases are characterized by relentless progression to end-stage renal failure. Sometimes, this progression is the result of continued activity of the initiating event. In many instances, the pathway to glomerular destruction involves poorly understood mechanisms. Putative mechanisms include glomerular hyperfiltration and hypertension, mesangial accumulation of serum-derived macromolecules, and activation of intraglomerular coagulation. Exactly how these possible mechanisms lead to the observed functional and structural deterioration are unclear. It is, however, generally accepted that a number of potent biological molecules participate in these processes. These molecules include lipid-derived mediators such as cyclooxygenase and lipoxygenase metabolites of arachidonate, platelet activating factor, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-B), angiotensin II, and interleukin-1. This Center Grant utilizes parallel techniques in physiology, pathology, pharmacology, biochemistry, cell biology, and molecular biology to define the specific mechanisms leading to glomerular and tubular dysfunction and progressive glomerular destruction. Multiple experimental techniques are applied to specific disease models representing two general categories: non- immunologic including renal mass ablation, puromycin- aminonucleoside nephrosis and adriamycin toxicity and immunologic, namely, renal allograft rejection. Standard glomerular micropuncture, as well as the newly developed technique of serial glomerular micropuncture allows for functional characterization of the disease process at varying time intervals. Morphologic quantitation of glomerular injury will be correlated with measurements of glomerular function. In vitro examination of glomerular preparations as well as cultured glomerular cell types will elucidate the roles of important biologic mediators in producing the functional and structural changes. Matrix compositions of sclerosing glomeruli will be defined and regulation of mRNA for matrix synthesis will be assessed via in situ hybridization techniques. The role that biologically important mediators play in altering epithelial cell functions will also be examined utilizing the in vitro tubule perfusion. The investigators in this program represent a unique blend of disciplines and sophisticated techniques that can be focused on one of the highest priority questions in kidney disease, i.e. the pathogenetic mechanisms leading to progressive nephron destruction.