TGF-beta signaling in the kidney

肾脏中的 TGF-β 信号传导

基本信息

批准号：
7389536
负责人：
MARY E CHOI
金额：
$ 33.81万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2000-06-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7389536
关键词：
Address Apoptosis Arts Cell Proliferation Cell physiology Cells Collagen Data Development Dominant-Negative Mutation End stage renal failure Epithelial Cells Experimental Models Extracellular Matrix Extracellular Matrix Proteins Fibrosis Gene Silencing Goals In Vitro Kidney Knockout Mice MAP Kinase Kinase Kinase MAP3K7 gene MAPK11 gene MAPK14 gene Mediating Mediator of activation protein Mitogen-Activated Protein Kinase Kinases Molecular Mus Pathogenesis Pathway interactions Personal Satisfaction Physiological Play Process Progressive Disease Protein Biosynthesis Protein Isoforms Proteins RNA RNA Interference Receptor Signaling Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Staging Stress Testing Tissues Transforming Growth Factor beta Tubular formation base cytokine fibrogenesis human MAPK13 protein human MAPK14 protein human RIPK1 protein human TGFB1 protein human TGFBR2 protein in vivo kidney cell mesangial cell mouse model novel receptor response response to injury

项目摘要

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-β1 (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 蛋白合成和积累的有效诱导剂，作为包括肾脏在内的多种组织中纤维发生的中心介质，在进行性疾病的发病机制中发挥着关键作用。然而，肾纤维化发病机制和进展为终末期肾衰竭的确切机制仍不完全清楚。我们之前的研究主要集中在 p38 丝裂原激活蛋白激酶 (MAPK)，这是一种主要的应激信号转导途径，可在肾细胞中被 TGF-B1 快速激活。我们已经确定 MKK3 是鼠系膜细胞和肾小管上皮细胞中 p38 MAPK 激活和 TGF-B1 刺激 pro-a1(l) 胶原所需的直接上游 MAPK 激酶。我们的假设是，MKK3-p38 α 和 p38 δ MAPK 信号转导途径是组织损伤反应的关键介质，其中 TGF-B1 发出信号 ECM 合成和积累，导致进行性肾纤维化。本提案将重点研究TGF-B1信号传导的细胞和分子机制，我们将进一步研究TGF-B1的MKK3-p38 MAPK信号通路的上游激活剂，并研究它们在肾小管上皮细胞损伤反应中的功能作用体外。将在肾纤维化的实验模型中寻找体内相关性。我们将采用最先进的方法，包括 TGF-B 受体的各种显性失活突变体、MAPK 和特定的 p38 亚型、通过使用短干扰 RNA (siRNA) 诱导的 RNAi（RNA 干扰）进行基因沉默，以及基因改造小鼠，各种 MAPK（特别是 MKK3）的无效小鼠。相关性：尽管 TGF-B1 在肾纤维化发展中的核心作用已得到充分证明，但不加区别地完全抑制 TGF-B1 作用的一般策略可能被证明是不谨慎的。本提案中的研究将产生重要且新颖的信息，进一步加深我们对 TGF-B1 信号转导分子机制的理解，使我们能够选择性地阻断发出 TGF-B1 有害作用信号的途径。