EPITHELIAL CELL DETERMINANTS OF GLOMERULOSCLEROSIS

这项建议的广泛目标是对肾小球的分析 上皮细胞缺陷作为进展性疾病的致病因素 肾小球硬化。肾小球的这种退变过程 毛细管束是一条重要的最终共同途径 在各种慢性肾功能衰竭患者中逐渐丧失肾功能 在肾脏疾病和许多肾敌的动物模型中， 免疫性和中毒性损伤。这一过程通常是独立的 最初的侮辱，在强度和时间上都不同于 在人类和实验中都是一个人对另一个人 动物。更好地了解负责的机制 这种类型的肾小球损害应该提供更合理的依据 进行旨在阻止破坏的治疗干预 肾小球微血管系统。虽然有几个血流动力学 结构调整与进步联系在一起。 肾小球硬化、精确的细胞事件和 导致关节闭塞的致病机制 微血管系统目前尚不清楚。这其中的一个关键因素 过程是对上皮细胞层完整性的破坏 毛细血管壁的一种情况，这种情况与 大小选择性渗透性缺陷与透明质酸蓄积 最终堵塞毛细管束的部分的物质。 据推测，高度发达的 分化的内脏上皮细胞发生在危重时期 胎儿和出生后早期的生长阶段，而这 发育受饮食和生长发育的影响很大 在这段时间起作用的刺激。在成年动物中， 上皮细胞失去复制能力并依赖于 专为随后的生理性或适应性肥大而设计 成长。这项提案中的研究旨在调查 正常情况下在该上皮细胞中发生的细胞事件 限制饮食条件下肾脏的发育 在器官发生过程中，以及在代偿性肥大和 其他形式的毛细血管壁损伤。拟议的调查 旨在建立定性或定量之间的关联 数量上皮细胞缺陷与进展性 肾实质功能丧失后的肾小球硬化。 放射自显影、形态测量和超微结构示踪剂 这些技术将被应用于建立良好的动物模型 人类疾病演变为进行性蛋白尿和 肾小球硬化。

The broad objective of this proposal is the analysis-of glomerular epithelial cell defects as pathogenetic factors in progressive glomerulosclerosis. This degenerative process of the glomerular capillary tuft is an important final common pathway that results in gradual loss of renal function in a variety of patients with renal disease and in many animal models of renoprival, immunological, and toxic injury. The process is often independent of the original insult and varies in intensity and time course from one individual to another both in humans and in the experimental animal. A better understanding of the mechanisms responsible for this type of glomerular damage should provide a more rational basis for therapeutic interventions aimed at arresting the destruction of the glomerular microvasculature. Although several hemodynamic and structural adaptations have been associated with progressive glomerulosclerosis, the precise cellular events and the pathogenetic mechanisms that result in occlusion of the microvasculature are at present unknown. A critical factor in this process is the damage co the integrity of the epithelial cell layer of the capillary wall, a condition that has been associated with size-selective permeability defects and accumulation of hyalin material which eventually occludes segments of the capillary tuft. It is hypothesized that the development of the highly differentiated visceral epithelial cell occurs during critical fetal and early postnatal phases of growth, and that this development is influenced significantly by dietary and growth stimuli that operate during this time. In the adult animal, the epithelial cell looses its capacity to replicate and relies exclusively on hypertrophy for subsequent physiologic or adaptive growth. The studies in this proposal are designed to investigate the cellular events that occur in this epithelium during the normal development of the kidney, under conditions of dietary restrictions during organogenesis, and following compensatory hypertrophy and other forms of capillary wall injury. The proposed investigations are aimed at establishing a correlation between qualitative or quantitative epithelial cell defects and progressive glomerulosclerosis following loss of functioning renal parenchyma. Autoradiographic, morphometric, and ultrastructural tracer techniques will be applied to well established animal models of human diseases that evolve with progressive proteinuria and glomerulosclerosis.