TNF Mediates Obstruction-Induced Renal Injury

TNF 介导梗阻性肾损伤

基本信息

批准号：
7481128
负责人：
KIRSTAN K MELDRUM
金额：
$ 13.34万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Obstruction of the upper urinary tract is a major clinical problem in both children and adults that results in progressive and ultimately irreversible renal damage. The majority of obstructive renal injury is attributed to renal cell loss via apoptosis and to progressive renal fibrosis. A number of inflammatory mediators have been implicated in the pathophysiology of renal obstruction, including tumor necrosis factor (TNF). TNF is a known cytotoxic agent capable of inducing apoptotic renal cell death in ischemic models of renal injury. While increased expression of TNF has been demonstrated following renal obstruction, the role of TNF in obstruction-induced renal cell apoptosis and fibrosis has not been elucidated. Our long term objectives are therefore to identify TNF as an important mediator of apoptosis and renal fibrosis during obstruction, and further, to develop a clinically relevant therapeutic strategy that will limit or prevent TNF induced obstructive renal injury. These goals will be accomplished using a rat model of unilateral renal obstruction by 1) determining the time course of renal cell apoptosis and fibrosis during obstruction, 2) determining the role of TNF in obstruction-induced renal apoptosis and fibrosis using the specific TNF inhibitor, soluble TNF receptor I (RTBP1), and 3) investigating the mechanisms of obstruction-induced renal TNF expression. For Specific Aim I, renal cortical tissue wilt be harvested following 1, 3, 7, or 14 days of obstruction, and assessed with regards to TNF expression and activity, TGF-beta expression, collagen deposition and fibrosis, and degree of apoptosis. Specific Aim II will assess the impact of TNF inhibition on obstruction-induced renal injury by investigating the parameters outlined in Aim I using rats that have been exposed to RTBP1 during the period of obstruction. Specific Aim III will assess the mechanisms of obstruction-induced renal TNF expression by investigating known regulators of TNF production, including nuclear factor kappaB and p38 mitogen activated protein kinase. Overall, the objective of this proposal is to apply and enhance the knowlegde gained by the applicant during her residency and fellowship training to develop a clinically relevant therapeutic approach to the treatment and prevention of obstructive renal injury

描述（由申请人提供）：上尿路梗阻是儿童和成人的一个主要临床问题，会导致进行性且最终不可逆的肾损伤。大多数阻塞性肾损伤归因于细胞凋亡导致的肾细胞损失和进行性肾纤维化。许多炎症介质与肾梗阻的病理生理学有关，包括肿瘤坏死因子（TNF）。 TNF是一种已知的细胞毒性剂，能够在肾损伤的缺血模型中诱导细胞凋亡。虽然肾梗阻后 TNF 表达增加，但 TNF 在梗阻诱导的肾细胞凋亡和纤维化中的作用尚未阐明。因此，我们的长期目标是确定 TNF 是梗阻期间细胞凋亡和肾纤维化的重要介质，并进一步开发临床相关的治疗策略，限制或预防 TNF 诱导的梗阻性肾损伤。这些目标将使用单侧肾梗阻的大鼠模型来实现，方法是：1) 确定梗阻期间肾细胞凋亡和纤维化的时间过程，2) 使用特定的 TNF 抑制剂确定 TNF 在梗阻诱导的肾细胞凋亡和纤维化中的作用，可溶性 TNF 受体 I (RTBP1)，3) 研究梗阻诱导的肾 TNF 表达的机制。对于具体目标 I，将在梗阻 1、3、7 或 14 天后收获肾皮质组织，并评估 TNF 表达和活性、TGF-β 表达、胶原沉积和纤维化以及细胞凋亡程度。具体目标 II 将通过使用在梗阻期间暴露于 RTBP1 的大鼠研究目标 I 中概述的参数，评估 TNF 抑制对梗阻性肾损伤的影响。具体目标 III 将通过研究已知的 TNF 产生调节因子（包括核因子 kappaB 和 p38 丝裂原激活蛋白激酶）来评估梗阻诱导的肾 TNF 表达的机制。总体而言，本提案的目的是应用和增强申请人在住院医师和进修培训期间获得的知识，以开发临床相关的治疗方法来治疗和预防梗阻性肾损伤