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-BETA 1（TGF-SS1）是一种多效性细胞因子，它控制多种细胞功能，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。 TGF-SS1作用是通过TGF-SS I型（TSSRI）和II型（TSSRII）受体介导的，以激活细胞内途径。许多中心问题仍然与不同的受体如何以细胞特异性和特定于上下文的方式介导TGF-SS1信号以引起多个细胞反应。我们研究的总体目的是了解肾脏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控和功能作用。我们的假设是，自噬代表了通过抑制凋亡和促进肾细胞存活来预防肾脏损伤的适应性应激反应，而TGF-SS1通过调节自噬来发挥细胞保护作用。此外，我们假设通过TAK1-MKK3-P38通过TGF-SS1信号传导是组织损伤反应的关键介体，其中TGF-SS1调节自噬蛋白，从而防止细胞凋亡和过度ECM积累。该建议将重点介绍通过TAK1在肾细胞中通过TAK1进行TGF-SS1信号传导的机制和功能作用，以及自噬的调节及其在肾纤维化实验模型中的生理功能作用。具体目的是：特定目标1：确定肾细胞中TGF-SS1信号传导的机理和功能作用。在肾细胞中特定目标2：确定肾细胞中TGF-SS1引起的自噬的调控和功能。特定目的3：确定自噬在肾纤维化实验模型中的体内生理功能作用。我们将采用最先进的方法，包括信号过滤分子的各种主要负突变体，MAPK，重点关注TAK1-MKK3信号轴，使用短的干扰RNA（siRNA）和遗传变化的小鼠，null小鼠的null小鼠，MKK3，cave3，cavelin和cavelin and covelin and thee covelin和bec lc and null小鼠的基因沉默。相关性：尽管TGF-SS1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-SS1动作的一般策略可能被证明是不明智的。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-SS1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-SS1的有害影响的途径。