Interstital Cell COXs in Renal Development and Disease

间质细胞 COX 在肾脏发育和疾病中的作用

• 批准号: 6675101
• 负责人: CHUAN-MING HAO
• 金额: $ 15.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-23 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675101
• 关键词: connective tissue cells; diabetic nephropathy; enzyme activity; gene deletion mutation; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; kidney function; laboratory mouse; nephrogenesis; polycystic kidney; prostaglandin endoperoxide synthase; prostaglandins; renal tubule; tissue /cell culture

DESCRIPTION (provided by applicant): Of all organs tested, the kidney exhibits the greatest level of expression of the inducible form of cyclooxygenase-2 (COX2) (Guan Am J. Physiol 1997), and within the kidney, the vast majority of COX2 resides in the interstitial cell. The interstitial cell is situated between the renal microvascular and epithelial compartments and so, COX2 derived prostaglandins elaborated by medullary interstitial cells are in an ideal location to modulate the functions of both renal tissues. Accumulating evidence suggests that renal interstitial/stromal cells are involved in virtually all functions of healthy kidney, and in many pathological events of the kidney [Grupp, 1999 #144]. However because COX2 is also expressed in the renal macula densa and COX1 is expressed in the collecting duct, the exact role of these renal interstitial cell COX2 derived prostanoids in the kidney is not precisesly known. The present proposal will focus on the role of renal interstitial/stromal COX mediated prostanoids in normal and diseased kidney including diabetic and polycystic kidney disease. Elucidating the bio-activity of renal prostaglandins will be important not only in understanding the maintenance of normal renal function but also in determining their potential as therapeutic targets in disease. The proposed studies will have two specific aims: Specific Aim 1: Generating and characterizing renal interstitial cell selective COX2 deficient mouse. Conventional COX2 gene disruption results in kidney dysgenesis, suggesting COX2 plays an important role in the kidney development, it remains uncertain whether interstitial or epithelial (i.e. nacent macula densa) derived COX2 is necessary for normal renal development. Futhermore examination of the role of COX2 in the adult COX2 null mouse is complicated by this renal dysgensis. Conditional COX2 knockout mice will allow this problem to be circumvented. Furthermore, the conditional COX2 knockout mouse will make it possible to study selectively the role of renal interstitial cell COX2 in the kidney. Specific Aim 2: Examine the role of renal interstitial COX2 and COX1 in maintenance of normal function and in the pathogenesis of disease such as diabetic nephropathy and polycystic kidney disease. The proposed studies will examine the effect of selective renal interstitial cell COX2 deletion on the (1) ability of renal papilla to survive hypertonic stress; (2) development of diabetic kidney disease; (3) on rate of expansion of cyst.

描述（由申请人提供）：在所有检测的器官中，肾脏表现出最高水平的诱导型环氧合酶-2（COX 2）表达（Guan Am J. Physiol 1997），并且在肾脏内，绝大多数COX 2存在于间质细胞中。间质细胞位于肾微血管和上皮隔室之间，因此，由髓质间质细胞加工的C 0X 2衍生的胡萝卜素处于调节两种肾组织功能的理想位置。越来越多的证据表明，肾间质/基质细胞参与健康肾脏的几乎所有功能，并参与肾脏的许多病理事件[Grupp，1999 #144]。然而，由于COX 2也在肾致密斑中表达，COX 1在集合管中表达，这些肾间质细胞COX 2衍生的前列腺素类在肾脏中的确切作用尚不确切。目前的建议将集中在肾间质/间质考克斯介导的前列腺素类在正常和患病的肾脏，包括糖尿病和多囊肾疾病的作用。阐明肾胰头素的生物活性不仅在理解正常肾功能的维持方面，而且在确定其作为疾病治疗靶点的潜力方面都是重要的。拟议的研究将有两个具体目标： 具体目的1：产生和表征肾间质细胞选择性COX 2缺陷小鼠。常规COX 2基因破坏导致肾脏发育不全，表明COX 2在肾脏发育中起重要作用，但尚不确定间质或上皮（即致密斑）来源的COX 2是否是正常肾脏发育所必需的。在成年COX 2缺失小鼠中COX 2作用的荧光检测因这种肾发育不良而复杂化。有条件的COX 2基因敲除小鼠将使这个问题得以规避。此外，条件性COX 2基因敲除小鼠将有可能选择性地研究肾间质细胞COX 2在肾脏中的作用。 具体目标二：检查肾间质COX 2和COX 1在维持正常功能以及糖尿病肾病和多囊肾等疾病发病机制中的作用。拟议的研究将检查选择性肾间质细胞COX 2缺失对（1）肾乳头在高渗应激中存活的能力;（2）糖尿病肾病的发展;（3）囊肿扩张速率的影响。