BIOLOGY OF PROGRESSIVE NEPHRON DESTRUCTION

许多肾脏疾病的特点是不断进展 到终末期肾衰竭 有时候，这种进展是 这是初始事件持续活动的结果。 在许多 在某些情况下，肾小球破坏的途径涉及不良 了解机制。 假定的机制包括肾小球 高滤过和高血压，系膜积聚 血清衍生的大分子，以及肾小球内 凝血 这些可能的机制是如何导致 观察到的功能和结构退化尚不清楚。 它 然而，人们普遍认为，许多有效的生物学 分子参与这些过程。 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-β）、血管紧张素II和 白细胞介素-1。 该中心赠款利用并行技术， 生理学，病理学，药理学，生物化学，细胞生物学， 和分子生物学来确定导致 肾小球和肾小管功能障碍以及进行性肾小球 杀伤性 多种实验技术被应用于 代表两大类的特定疾病模型： 免疫治疗包括肾肿块消融、嘌呤霉素- 氨基糖苷类肾病和阿霉素毒性 免疫学，即肾移植排斥。 标准 肾小球微穿刺，以及新开发的 连续肾小球微穿刺技术允许 疾病过程在不同时间的功能表征 的间隔 肾小球损伤的形态学定量将是 与肾小球功能的测量相关。 体外 肾小球制备物和培养物的检查 肾小球细胞类型将阐明重要的作用， 生物介质产生的功能和结构 变化 硬化肾小球的基质成分将是 定义和调节mRNA的基质合成将是 通过原位杂交技术进行评估。 的作用 生物学上重要的介质在改变上皮细胞 还将利用体外小管检查功能 灌注。 该项目的调查人员代表了一种独特的 融合了学科和复杂的技术， 专注于肾脏疾病中最重要的问题之一， 即进行性肾单位的发病机制 杀伤性

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.