EPITHELIAL CELL DETERMINANTS OF GLOMERULOSCLEROSIS

这项建议的主要目的是分析肾小球疾病的发生， 上皮细胞缺陷是进行性甲状腺炎的致病因素 肾小球硬化 肾小球的退化过程 毛细血管丛是一个重要的最终共同途径， 肾功能逐渐丧失的患者， 肾病和在许多肾移植的动物模型中， 免疫和毒性损伤。 这个过程往往是独立的 原始侮辱的强度和时间过程不同， 无论是在人类还是在实验中， 动物 更好地了解造成这些问题的机制 这种类型的肾小球损伤应该提供了一个更合理的基础， 进行治疗性干预， 肾小球微血管系统。 虽然几个血流动力学 结构性适应与进步有关 肾小球硬化症，精确的细胞事件和 致病机制，导致闭塞的 微脉管系统目前是未知的。 其中一个关键因素是 这一过程是对上皮细胞层完整性的破坏 毛细血管壁，一个条件，已与 尺寸选择性渗透性缺陷和透明质的积累 最终堵塞毛细管簇的片段的材料。 据推测，高度发达的 分化的内脏上皮细胞发生在 胎儿和出生后早期的生长阶段， 发育受饮食和生长的显著影响 在这段时间内运作的刺激。 在成年动物中， 上皮细胞失去了复制能力， 专门用于随后的生理性或适应性肥大 增长 本提案中的研究旨在调查 正常情况下上皮细胞中发生的细胞事件 肾脏的发育，在饮食限制的条件下 在器官形成过程中，以及在代偿性肥大之后， 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相关性， 定量上皮细胞缺陷和进行性 肾实质功能丧失后的肾小球硬化。 放射自显影、形态测定和超微结构示踪剂 技术将被应用于良好建立的动物模型， 发展为进行性蛋白尿的人类疾病 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.