URINARY CRYSTAL-RENAL CELL INTERACTIONS IN UROLITHIASIS

候选人的长期目标是识别细胞和 调节早期事件的分子机制 肾结石。候选人和他的赞助人F·加里博士 Toback，制定了一项促进收购的教育计划 进行调查所需的调查技能和技巧 最先进的肾脏细胞生理学研究，并提供 有机会将这些研究直接应用于患有 肾结石。将候选人发展成为独立的 调查员将在收到临床报告后得到便利。 调查员奖。在提议的颁奖过程中，他 将扩大之前与已建立的合作伙伴的合作 芝加哥大学基础科学的研究人员， 以及发起新的合作来扩展他的研究 进入新的领域。候选人将拥有独特的优势： 与芝加哥大学肾结石项目密切接触 也是公认的肾结石专家。在过去的两年半内 多年来，这位候选人开发了一种组织培养模型 肾结石并用它来表征肾上皮细胞如何 细胞与细胞中最常见的晶体相互作用 尿液和结石，一水合草酸钙(COM)。他发现 COM晶体附着在肾细胞表面，经历内吞作用， 并启动后续的细胞反应，如早期基因 表达、细胞骨架重组和DNA合成。一个 新的观察，Tamm-Horsfall糖蛋白(THP)，最 人尿中丰富的蛋白质，抑制COM的内吞作用 将对晶体进行深入研究，因为最近的研究表明 这种蛋白质似乎已经失去了其抑制功能 复发性肾结石的特定患者。的具体目标 本项目的目的是：1)确定一个特定的表面受体(S) 肾上皮细胞上的COM晶体。2)描述 THP与肾上皮细胞的相互作用。3)调查THP 肾结石患者的结构和功能。4)定义 调节黏附素和随后的COM内吞作用的因素 水晶。5)确定结构和功能上的变化 肾上皮细胞的质膜、细胞骨架和细胞核 COM晶体附着和内吞作用后的细胞。6) 确定COM晶体的黏附和/或内吞是否会导致 肾细胞释放自分泌/旁分泌因子。 7)确定阻碍个别步骤的潜在治疗剂 在细胞和分子事件的级联中，当 COM晶体与肾上皮细胞相互作用。实现 这些特定的目标将增加对肾脏如何 上皮细胞对尿液晶体有反应。对这些问题的解释 细胞和分子水平的过程可以帮助实现 制定合理的新治疗策略的长期目标 防止肾结晶滞留和结石的形成。

The candidate's long-term goal is to identify cellular and molecular mechanisms that mediate the early events in nephrolithiasis. The candidate and his sponsor, Dr. F. Gary Toback, have developed an educational plan which foster acquisition of the investigative skills and techniques necessary to conduct state-of-the-art research in renal cell physiology, and provides the opportunity to apply these studies directly to patients with nephrolithiasis. Development of the candidate into an independent investigator will be facilitated b receipt of a Clinical Investigator Award. During the course of the proposed award, he will expand previous collaborative efforts with established investigators in the basic sciences at the University of Chicago, as well as initiate new collaborations which extend his studies into new fields. The candidate will have the unique advantage of close contact with the University of Chicago Kidney Stone Program and a recognized expert in nephrolithiasis. During the past 2 1/2 years the candidate has developed a tissue culture model of nephrolithiasis and used it to characterize how renal epithelial cells respond to an interaction with the most common crystal in urine and stones, calcium oxalate monohydrate (COM). He found that COM crystals adhere to the renal cell surface, undergo endocytosis, and initiate subsequent cellular response such as early gene expression, cytoskeletal reorganization, and DNA synthesis. A novel observation, that Tamm-Horsfall glycoprotein (THP), the most abundant protein in human urine, inhibits endocytosis of COM crystals will be studied in depth because recent work reveals that this protein appears to have lost its inhibitory function in specific patients with recurrent nephrolithiasis. Specific aims of the project are to: 1) Define a specific surface receptor (s) for COM crystal on renal epithelial cells. 2) Characterize the interaction of THP with renal epithelial cells. 3) Investigate THP structure and function in patients with nephrolithiasis. 4) Define factors that regulate adhesin and subsequent endocytosis of COM crystals. 5) Identify structural and functional alteration in the plasma membrane, cytoskeleton, and nucleus of renal epithelial cells following attachment and endocytosis of COM crystals. 6) Determine if adhesion and/or endocytosis of COM crystals induces release of autocrine/paracrine factors from renal cells. 7)Identify potential therapeutic agents that block individual steps in the cascade of cellular and molecular events set in motion when a COM crystal interacts with a renal epithelial cell. Achieving these specific aims will increase understanding of how kidney epithelial cell respond to urinary crystals. Elucidation of these processes at the cellular and molecular level could help attain the long-term goal of formulating rational new therapeutic strategies to prevent renal crystal retention and the formation of calculi.