Role of Tamm-Horsfall Protein in Urinary Tract Defense

Tamm-Horsfall 蛋白在尿路防御中的作用

基本信息

批准号：
9293293
负责人：
XUE-RU WU
金额：
$ 38.14万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293293
关键词：
Age-Months American Apatites Apoptosis Basement membrane Calcified Calcinosis Calcium Calcium Oxalate Caveolins Chemicals Clathrin Clinical Crystallization Cytoplasm Defect Deposition Disease Electrons Environment Epithelial Cells Event Failure Gender Gene Dosage Genes Genetically Engineered Mouse Goals Human Hydroxyapatites Hyperoxaluria In Vitro Inflammation Kidney Kidney Calculi Kidney Papilla Knockout Mice Laboratories Lead Lesion Light Location Lysosomes Medical Molecular Mus Names Nephrolithiasis Pain Papillary Pathogenesis Pathologic Pathway interactions Patients Phagocytes Physiological Prevention strategy Process Proteins Recurrence Role Series Specimen Spectrum Analysis Structure of ascending limb of Henle&apos s loop Testing Thick Transmission Electron Microscopy Tube Tubular formation UMOD gene Urinary tract Ursidae Family Wild Type Mouse Woman absorption calcification calcium phosphate cytotoxicity experimental study hypercalciuria improved in vivo insight interstitial knockout animal laser capture microdissection lifetime risk macromolecule major urinary proteins men mouse model novel osteopontin prevent public health relevance renal calcium response spatial relationship tandem mass spectrometry tool uptake urinary

项目摘要

DESCRIPTION (provided by applicant): Kidney stone is an exceedingly common disease. The lifetime risk of developing a kidney stone is about one in eight in American men and one in twenty in American women. An overwhelming majority of the kidney stones are recurrent, adding significantly to the pain, suffering and medical expenses. Kidney stone formation or nephrolithiasis is believed to be a multistage process, but precisely how each step takes place in a physiological environment remains poorly understood to date. In the past, attempts to understand the pathogenesis of kidney stone depended heavily on in vitro experimentation and human specimens harboring full-fledged stones. While extremely necessary, these approaches alone do not allow a comprehensive analysis of the full-spectrum of the lithogenic process from the beginning to the end. Over the last 10 years, our laboratory has been developing genetically engineered mouse models to characterize the sequential steps of nephrolithiasis. In particular, we inactivated the gene encoding Tamm-Horsfall protein (THP; also named uromodulin), a major urinary protein made by kidney's thick ascending limb of loop of Henle. We found that these knockout (KO) mice are prone to developing intra-renal calcinosis that bears strong resemblance in many respects to human patients bearing idiopathic calcium oxalate stones. The main goal of this renewal proposal is to significantly expand and deepen our understanding of the molecular and cellular mechanisms whereby defects of THP lead to intra-renal calcification. Specifically, we will investigate how interstitial calcification in THP KO mice originate and evolve in a spatial and temporal manner by performing ultra- structural and chemical and protein composition analyses. We will examine how renal epithelial cells uptake the intratubular crystals and whether and how this leads to cytotoxicity. We will determine whether formation of bona-fide kidney stones in THP KO mice relies on heightened urinary supersaturation of calcium phosphate or calcium oxalate by generating compound, genetically engineered mice that naturally develop these conditions. Together, these interconnected and mutually enforcing studies should offer novel insights into how kidney stones develop and how they can be better prevented.

描述（由适用提供）：肾结石是一种极为常见的疾病。在美国男性中，生长肾结石的终生风险约为八分之一，在美国女性中占了二十个。绝大多数肾结石都经常出现，从而大大增加了痛苦，痛苦和医疗费用。据信肾结石形成或肾石器症是一个多阶段的过程，但是迄今为止，在生理环境中，每个步骤都在生理环境中的理解仍然很差。过去，试图严格了解肾结石的发病机理，严重依赖于体外实验和具有全面石头的人类标本。尽管非常必要，但仅这些方法就不允许从头到尾对岩性过程的全光谱进行全面分析。在过去的十年中，我们的实验室一直在开发一般的工程小鼠模型，以表征肾石石症的顺序步骤。特别是，我们灭活了编码Tamm-Horsfall蛋白的基因（THP；也称为泌尿瘤蛋白），这是一种由肾脏浓密的Henle环升升升的主要尿蛋白。我们发现，这些敲除（KO）小鼠容易发育肾脏内钙化，在许多方面对带有特发性草酸钙结石的人类患者具有很大的相似之处。该更新建议的主要目标是显着扩展和加深我们对分子和细胞机制的理解，从而导致THP的缺陷导致肾脏内计算。具体而言，我们将通过执行超结构和化学和蛋白质组成分析来研究THP KO小鼠中的间质计算以空间和临时的方式产生和进化。我们将研究肾上皮细胞如何摄取细胞内晶体以及这是否以及如何导致细胞毒性。我们将确定通过产生化合物，自然发展这些疾病的化合物，基因设计的小鼠，是否依赖于THP KO小鼠中真正的肾结石的形成。这些相互联系和相互执行的研究共同提供了有关肾结石如何发展以及如何更好地预防肾脏的新见解。