TGF-beta signaling in the kidney

肾脏中的 TGF-β 信号传导

• 批准号: 8820727
• 负责人: MARY E CHOI
• 金额: $ 19.57万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820727
• 关键词: TGF; beta; signaling; kidney

DESCRIPTION (provided by applicant): Transforming growth factor-beta 1 (TGF-ss1) is a pleiotropic cytokine which controls multiple cellular functions including cell proliferation, differentiation, apoptosis, and extracellular matrix (ECM) synthesis. TGF-ss1 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. TGF-ss1 actions are mediated via TGF-ss type I (TssRI) and type II (TssRII) receptors to activate intracellular pathways. Many central questions remain relating to how the distinct receptors mediate TGF-ss1 signals in a cell-specific and context-specific manner to elicit multiple cellular responses. The overall objective of our research is to understand the cellular and molecular mechanisms of renal injury and fibrosis. The major goals are to investigate the mechanisms of TGF-ss1 signaling pathways and their regulation and functional role in injury responses in the kidney. Our hypothesis is that autophagy represents an adaptive stress response to protect against renal injury by inhibiting apoptosis and promoting renal cell survival, and that TGF-ss1 exerts cytoprotective effects via regulating autophagy. Furthermore, we hypothesize that TGF-ss1 signaling via TAK1- MKK3-p38 is the critical mediator of tissue injury response in which TGF-ss1 regulates autophagy proteins which in turn prevents apoptosis and excessive ECM accumulation. This proposal will focus on examining the mechanism and functional role of TGF-ss1 signaling via TAK1 in renal cells, and the regulation of autophagy and its physiological functional role in an experimental model of renal fibrosis. The Specific Aims are: Specific Aim 1: To determine the mechanism and functional role of TGF-ss1 signaling via TAK1 in renal cells Specific Aim 2: To determine the regulation and function of autophagy induced by TGF-ss1 in renal cells. Specific Aim 3: To determine the in vivo physiological functional role of autophagy in an experimental model of renal fibrosis. We will employ state-of-the art approaches including a variety of dominant negative mutants of the signal transducing molecules, the MAPKs, focusing on the TAK1-MKK3 signaling axis, gene silencing by the use short interfering RNA (siRNA), and genetically altered mice, the null mice for the various TAK1, MKK3, Caveolin-1, and the autophagy genes, LC3 and Beclin 1. Relevance: Although the central role of TGF-ss1 in the development of renal fibrosis is well documented, general strategies to indiscriminately inhibit TGF-ss1 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-ss1 signal transduction, that we may be able to selectively block the pathway that signals the deleterious effects of TGF-ss1.

描述（由申请人提供）：转化生长因子-β1（TGF-ss1）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-ss1 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。 TGF-ss1 作用通过 TGF-ss I 型 (TssRI) 和 II 型 (TssRII) 受体介导，激活细胞内通路。许多核心问题仍然与不同受体如何以细胞特异性和环境特异性方式介导 TGF-ss1 信号以引发多种细胞反应有关。我们研究的总体目标是了解肾损伤和纤维化的细胞和分子机制。主要目标是研究 TGF-ss1 信号通路的机制及其在肾脏损伤反应中的调节和功能作用。我们的假设是，自噬代表一种适应性应激反应，通过抑制细胞凋亡和促进肾细胞存活来防止肾损伤，并且 TGF-ss1 通过调节自噬发挥细胞保护作用。此外，我们假设通过 TAK1-MKK3-p38 的 TGF-ss1 信号传导是组织损伤反应的关键介质，其中 TGF-ss1 调节自噬蛋白，从而防止细胞凋亡和过度的 ECM 积累。该提案将重点研究肾细胞中通过 TAK1 进行 TGF-ss1 信号传导的机制和功能作用，以及肾纤维化实验模型中自噬的调节及其生理功能作用。具体目标是： 具体目标 1：确定肾细胞中通过 TAK1 进行 TGF-ss1 信号传导的机制和功能作用。 具体目标 2：确定肾细胞中 TGF-ss1 诱导的自噬的调节和功能。具体目标 3：确定肾纤维化实验模型中自噬的体内生理功能作用。我们将采用最先进的方法，包括信号转导分子 MAPK 的各种显性失活突变体，重点关注 TAK1-MKK3 信号轴、通过使用短干扰 RNA (siRNA) 进行基因沉默以及基因改变小鼠，各种 TAK1、MKK3、Caveolin-1 和自噬基因 LC3 和 Beclin 1 的无效小鼠。 相关性：尽管 TGF-ss1 的核心作用肾纤维化发展过程中的相关性已被充分记录，但不加区别地完全抑制 TGF-ss1 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-ss1 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-ss1 有害作用信号的途径。