TGF-beta signaling in the kidney

肾脏中的 TGF-β 信号传导

• 批准号: 7105780
• 负责人: MARY E CHOI
• 金额: $ 30.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105780
• 关键词: RNA interference; biological signal transduction; fibrosis; genetically modified animals; glomerulosclerosis; growth factor receptors; laboratory mouse; laboratory rat; mitogen activated protein kinase; molecular pathology; mutant; protein isoforms; receptor expression; transforming growth factors

DESCRIPTION (provided by applicant): Background: Transforming growth factor-beta 1 (TGF-B1) is a pleiotropic cytokine which controls multiple cellular functions including cell proliferation, differentiation, apoptosis, and extracellular matrix (ECM) synthesis. TGF-B1 is a potent inducer of ECM protein synthesis and accumulation, and plays a key role in the pathogenesis of progressive diseases as a central mediator of fibrogenesis in a variety of tissues, including the kidney. However, the precise mechanisms responsible for the pathogenesis of renal fibrosis and progression to end-stage renal failure remain incompletely understood. Our previous studies have focused on the p38 mitogen-activated protein kinase (MAPK), a major stress signal transducing pathway that is rapidly activated by TGF-B1 in renal cells. We have identified MKK3 as the immediate upstream MAPK kinase required for activation of p38 MAPK and stimulation of pro-a1(l) collagen by TGF-B1 in murine mesangial cells and tubular epithelial cells. Our hypothesis is that the MKK3-p38 alpha and p38 delta MAPK signal transduction pathway is the critical mediator of tissue injury response in which TGF-B1 signals ECM synthesis and accumulation leading to progressive renal fibrosis. This proposal will focus on examining the cellular and molecular mechanism of TGF-B1 signaling, and we will further investigate the upstream activators of MKK3-p38 MAPK signaling pathway for TGF-B1, and examine their functional role in injury responses in renal tubular epithelial cells in vitro. In vivo correlates will be sought in an experimental model of renal fibrosis. We will employ state-of-the art approaches including a variety of dominant negative mutants of TGF-B receptors, the MAPKs and specific p38 isoforms, gene silencing by the use of RNAi (RNA interference) induced by short interfering RNA (siRNA), and genetically altered mice, the null mice for the various MAPKs, particularly the MKK3. Relevance: Although the central role of TGF-B1 in the development of renal fibrosis is well documented, general strategies to indiscriminately inhibit TGF-B1 actions altogether may prove to be imprudent. The studies in this proposal will yield important and novel information in furthering our understanding of the molecular mechanisms of TGF-B1 signal transduction, that we may be able to selectively block the pathway that signals the deleterious effects of TGF-B1.

描述（由申请人提供）：背景：转化生长因子-Beta 1（TGF-B1）是一种多效性细胞因子，控制多种细胞功能，包括细胞增殖，分化，凋亡和细胞外基质（ECM）合成。 TGF-B1是ECM蛋白质合成和积累的有效诱导剂，并且在进行性疾病的发病机理中起关键作用，作为包括肾脏在内的多种组织中纤维化的中心介体。然而，导致肾纤维化发病机理和发展为终末期肾衰竭的确切机制尚不完全了解。我们以前的研究集中在p38促丝分裂原激活的蛋白激酶（MAPK）上，这是一种主要的应力信号转导途径，在肾细胞中TGF-B1迅速激活。我们已经将MKK3确定为激活p38 MAPK所需的直接上游MAPK激酶，以及在鼠肾小管细胞和肾小管上皮细胞中TGF-B1刺激Pro-A1（L）胶原蛋白。我们的假设是MKK3-P38α和p38 Delta MAPK信号转导途径是组织损伤反应的关键介体，其中TGF-B1信号ECM合成和积累导致肾脏肾纤维化。该建议将着重研究TGF-B1信号传导的细胞和分子机制，我们将进一步研究MKK3-P38 MAPK信号通路的上游激活剂，用于TGF-B1，并检查其在体外肾小管上皮细胞中肾小管上皮细胞中其功能作用。体内相关性将在肾纤维化的实验模型中寻求。我们将采用最先进的方法，包括TGF-B受体的各种显性负突变，MAPK和特定的P38同工型，通过使用短暂干扰RNA（siRNA）引起的RNAi（RNA干扰）的基因沉默，以及遗传改变的小鼠，null小鼠，null小鼠，尤其是MKK3。相关性：尽管TGF-B1在肾纤维化发展中的核心作用已被充分证明，但完全抑制TGF-B1动作的一般策略可能被证明是不明显的。该提案中的研究将产生重要和新颖的信息，以进一步了解我们对TGF-B1信号转导的分子机制的理解，我们可能能够选择性地阻止向TGF-B1的有害作用发出有害影响的途径。