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Targeting proteotoxic stress responses in liver fibrosis

靶向肝纤维化中的蛋白毒性应激反应

基本信息

批准号：
9333852
负责人：
Pranoti Mandrekar
金额：
$ 38.98万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-20 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333852
关键词：
Alcohols Candidate Disease Gene Cell physiology Cells Cellular Stress Chronic Cirrhosis Clinical Collagen Type I Data Dependence Development Endoplasmic Reticulum Exposure to Extracellular Matrix Fibroblasts Fibrosis Gene Targeting HSF1 HSP 90 inhibition Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hepatic Stellate Cell Hepatitis B Hepatitis C In Vitro Inflammation Inflammatory Injury Investigation Knock-out Knockout Mice Knowledge Link Liver Liver Fibrosis Mediating Modeling Molecular Chaperones Morbidity - disease rate Myofibroblast Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathogenicity Pathway interactions Plasmids Play Primary carcinoma of the liver cells Process Property Proteins Recovery Regulation Reporting Resolution Role Signal Transduction Stimulus Stress Testing Therapeutic Viral hepatitis Wound Healing biological adaptation to stress cytokine design effective therapy fibrogenesis global health in vivo inhibitor/antagonist mortality nanoparticle nonalcoholic steatohepatitis novel overexpression pre-clinical proteostasis proteotoxicity public health relevance response stellate cell stress protein transcription factor

项目摘要

ABSTRACT Liver fibrosis is linked to inflammation and deregulated wound healing response, triggered by chronic exposure to various types of insults including alcohol, obesity, NASH and viral hepatitis. Recently emerging liver therapies directed to eliminate the pathogenic agent suggest promise in resolving fibrosis. However, to design anti-fibrotic therapeutic strategies we need a better understanding of the pathogenesis of fibrosis. Accumulation of extracellular matrix is the hallmark of hepatic fibrosis. Hepatic stellate cells (HSCs) are activated by pro-fibrogenic stimuli and are the main ECM producing cells in the liver. The role of oxidative stress and inflammatory cytokines in HSC activation has been under extensive investigation. Targeting stress pathways to inactivate HSCs is an attractive therapeutic strategy and crucial to effective treatment. Stress induced transcription factor and master regulator of proteotoxic responses, HSF1 mediates induction of HSP90 and HSP70, stress chaperones important in inflammatory signaling and likely to play a role in HSC activation and reversion, respectively. Our preliminary data show that deficiency of HSF1, unable to induce HSP70 promotes HSC activation and fibrosis and moreover, is unable to resolve HSC activation and fibrosis in a model of fibrosis recovery. Increased cytosolic HSP90AA1 and endoplasmic reticulum (ER), HSP90B1/Grp94/gp96 in fibrotic livers may contribute to fibrogenesis. Targeting HSP90, using a specific inhibitor, 17-DMAG, which induces HSF1 activation and downstream HSP70, will delineate the role of HSF1-HSP70 in inactivation of hepatic stellate cells. We hypothesize that HSF1 inactivity and HSP90 induction during stellate cell activation contributes to liver fibrosis, whereas induction of HSF1 and HSPA1A/HSP70 contributes to resolution of fibrosis. The Specific Aims are- 1) To unravel the role of stress mediated transcription factor, HSF1 on regulation of liver fibrosis by: Examining the effect of stellate cell specific knock-out of HSF1 on fibrogenesis; Testing effect of HSF1-plasmid nanoparticles on fibrosis resolution; Evaluating longitudinal expression, activity and novel target genes regulated by HSF1 during fibrosis and resolution. 2) To assess whether targeting HSP90AA1 (cytosolic) and/or HSP90B1/Grp94/gp96(ER) regulates stellate cell activation and fibrogenesis by: Evaluating the induction of HSP90AA1 and gp96 during stellate cell activation; Investigating effect of hsp90 inhibitor, 17-DMAG on liver fibrosis; Determining effect of stellate cell-specific inhibition of gp96 and HSP90 in vivo, on hepatic fibrosis. 3) To investigate importance of HSF1 induced HSP70 in stellate cell function by: Determining induction of Hsp70 and its dependence on HSF1, during resolution of fibrosis; Investigating whether overexpression of HSP70 inactivates HSC and resolves fibrosis; Evaluating HSF1-HSP70 axis during 17-DMAG treatment on HSC activation and fibrosis. Our proposed studies will unravel the role of HSF1 mediated stress pathways and chaperones in stellate cell activation and fibrosis.

摘要