TGF-beta signaling in the kidney

肾脏中的 TGF-β 信号传导

基本信息

批准号：
8466956
负责人：
MARY E CHOI
金额：
$ 17.84万
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 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466956
关键词：
Address Apoptosis Autophagocytosis Binding Binding Proteins Biological Cell Nucleus Cell Proliferation Cell Survival Cell physiology Cell surface Cells Chronic Kidney Failure Collagen Type I Complex Cytoplasmic Protein Cytoprotection Data Development Dissection Dominant-Negative Mutation Down-Regulation End stage renal failure Epithelial Cells Excision Exhibits Experimental Models Extracellular Matrix Extracellular Matrix Proteins Fibrosis Gene Silencing Genes Goals Growth Factor Homeostasis In Vitro Injury Kidney Kidney Failure Knockout Mice Lead MAPK14 gene Mediating Mediator of activation protein Mitogen-Activated Protein Kinase Kinases Modeling Molecular Mus Nuclear Proteins Organelles Pathogenesis Pathway interactions Phosphotransferases Physiological Play Process Progressive Disease Protein Biosynthesis Proteins RNA Receptor Signaling Recycling Regulation Research Role Scheme Signal Pathway Signal Transduction Signal Transduction Pathway Testing Therapeutic Intervention Tissues Transforming Growth Factor beta Tubular formation Ureteral obstruction Wound Healing base biological adaptation to stress caveolin 1 cytokine fibrogenesis human MAPK14 protein human TGFB1 protein in vivo in vivo Model kidney cell mesangial cell novel novel therapeutic intervention prevent receptor response response to injury tissue regeneration

项目摘要

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.