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.

Public Health Relevance

Our research centers on understanding the mechanisms of TGF-ss1 actions. By careful dissection of the complex TGF-ss signal transduction pathways, our goal is to be able to selectively block the pathway that signals the deleterious effects of TGF-ss1, and provide a novel therapeutic approach to prevent development of progressive renal fibrosis and ensuing kidney failure in chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057661-13
Application #
8466956
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2000-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$374,155
Indirect Cost
$164,267
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Lee, So-Young; Kim, Sung I; Choi, Mary E (2015) Therapeutic targets for treating fibrotic kidney diseases. Transl Res 165:512-30
Kim, Sung Il; Lee, So-Young; Wang, Zhibo et al. (2014) TGF-?-activated kinase 1 is crucial in podocyte differentiation and glomerular capillary formation. J Am Soc Nephrol 25:1966-78
Ding, Yan; Choi, Mary E (2014) Regulation of autophagy by TGF-?: emerging role in kidney fibrosis. Semin Nephrol 34:62-71
Kim, Sung Il; Na, Hee-Jun; Ding, Yan et al. (2012) Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-ýý1. J Biol Chem 287:11677-88
Ding, Yan; Kim, Jin Kuk; Kim, Sung Il et al. (2010) TGF-{beta}1 protects against mesangial cell apoptosis via induction of autophagy. J Biol Chem 285:37909-19
Kim, Sung Il; Kwak, Joon Hyeok; Na, Hee-Jun et al. (2009) Transforming growth factor-beta (TGF-beta1) activates TAK1 via TAB1-mediated autophosphorylation, independent of TGF-beta receptor kinase activity in mesangial cells. J Biol Chem 284:22285-96
Kwak, Joon Hyeok; Kim, Sung Il; Kim, Jin Kuk et al. (2008) BAT3 interacts with transforming growth factor-beta (TGF-beta) receptors and enhances TGF-beta1-induced type I collagen expression in mesangial cells. J Biol Chem 283:19816-25
Wang, Lin; Lee, Ji-Yang Sophie; Kwak, Joon Hyeok et al. (2008) Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction. Am J Physiol Renal Physiol 294:F508-17
Kim, Sung Il; Kwak, Joon Hyeok; Wang, Lin et al. (2008) Protein phosphatase 2A is a negative regulator of transforming growth factor-beta1-induced TAK1 activation in mesangial cells. J Biol Chem 283:10753-63
Kim, Sung Il; Kwak, Joon Hyeok; Zachariah, Mareena et al. (2007) TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am J Physiol Renal Physiol 292:F1471-8

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