Hepatoprotective Mechanisms of TTC39B Deficiency

TTC39B 缺陷的保肝机制

• 批准号: 10407976
• 负责人: Joanne Hsieh
• 金额: $ 15.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407976
• 关键词: Academic Medical Centers; Acids; Acute; Acyltransferase; Adult; Advisory Committees; Affect; Atherosclerosis; Automobile Driving; Blood; Cells; Child; Cholesterol; Clinical Research; Clinical Trials; Development; Diet; Disease; Ensure; Enzymes; Exhibits; Faculty; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Genotype; Goals; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Density Lipoprotein Cholesterol; Histologic; Human; Hydrolysis; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knockout Mice; Leukocytes; Lipids; Lipoproteins; Liver; Liver Fibrosis; Liver X Receptor; Liver diseases; Medicine; Mentors; Mentorship; Metabolic Diseases; Metabolism; Modeling; Mus; Pathogenesis; Phenotype; Phosphatidic Acid; Phospholipases A; Phospholipid Metabolism; Phospholipids; Play; Production; Research; Research Personnel; Resources; Role; SRE-1 binding protein; Serum; Signal Transduction; Steatohepatitis; Testing; Training; Wild Type Mouse; Work; adeno-associated viral vector; career development; design; effective therapy; genome wide association study; in vivo; inhibitor; inorganic phosphate; knock-down; lipid biosynthesis; lipid metabolism; liver injury; lysophosphatidic acid; member; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; overexpression; pediatric department; pediatric non-alcoholic fatty liver disease; prevent; receptor; research and development; success

Hepatoprotective Mechanisms of TTC39B Deficiency PI: Hsieh, Joanne Project Summary/Abstract This K01 application is designed to provide the necessary resources and training to transition Dr. Joanne Hsieh to full independence in the field of lipid metabolism in liver disease. The proposed work and training will be performed at Columbia University Medical Center (CUMC) in the Department of Medicine, which has demonstrated a commitment to junior faculty mentorship. She will be mentored by Dr. Alan Tall, who is a pre-eminent investigator in lipoprotein metabolism and atherosclerosis. With Dr. Joel Lavine in the Department of Pediatrics as her co-mentor, Dr. Hsieh will transition her focus towards non-alcoholic fatty liver disease (NAFLD). Dr. Lavine has an extensive record of clinical research in adult and pediatric NAFLD, and will be integral in Dr. Hsieh's training in building translational aims into her biomechanistically-focused research. Dr. Hsieh will continue her research on TTC39B, a novel gene significantly associated with HDL-cholesterol in human GWAS. Dr. Hsieh recently showed that deficiency in TTC39B conferred a dramatic protection from steatohepatitis in mice. This hepatoprotection was associated with inhibited sterol-regulatory element binding protein-1 (SREBP-1) activation and decreased lipogenic gene expression. The overall goal of the proposal to determine how decreased expression of specific lipogenic genes contributes the hepatoprotective effects of TTC39B deficiency. Dr. Hsieh will conduct the investigations in a diet-induced mouse model of steatohepatitis that exhibits many of the histological features observed in human NASH, including inflammatory cell infiltration and fibrosis. In the first aim, TTC39B's effect on SREBP-1 activation will be further explored mechanistically to understand the early pathogenesis of NAFLD. The first subaim will determine whether the SREBP-1 inactivation in TTC39B deficiency is driving the protection from steatohepatitis, while the second will investigate the role of phospholipid metabolism in this inactivation. The second aim will explore whether the suppression of phosphatidic acid signalling in TTC39B deficiency prevents the progression of NAFLD to the more severe non-alcoholic steatohepatitis (NASH). Dr. Hsieh's scientific research and career development will be further supported by members of her advisory board, including Dr. Muredach Reilly, Dr. Robert Schwabe, and Dr. Richard Deckelbaum. The mentoring and advisory team will help broaden Dr. Hsieh's approach to scientific hypothesis-testing and ensure her success as an independent investigator.

TTC39B缺陷PI的肝保护机制：HSIEH，JOANNE 项目摘要/摘要 该K01应用程序旨在为过渡提供必要的资源和培训 Joanne Hsieh博士在肝病中脂质代谢领域充分独立。这 拟议的工作和培训将在哥伦比亚大学医学中心（CUMC）进行 医学系表明了对初级教师的承诺 指导。她将受到艾伦·塔博士（Alan Tall）的指导，他是杰出的调查员 脂蛋白代谢和动脉粥样硬化。与乔尔·拉文（Joel Lavine）博士一起在儿科系 作为她的同事，Hsieh博士将把重点转移到非酒精性脂肪肝病上 （NAFLD）。 Lavine博士在成人和小儿NAFLD中有广泛的临床研究记录， 并将在Hsieh博士的培训中不可或缺 以生物力学为中心的研究。 Hsieh博士将继续对TTC39B的研究，这是一部小说 基因与人类GWA中的HDL-胆固醇显着相关。 Hsieh博士最近展示了 TTC39B的缺乏赋予了小鼠的脂肪性肝炎，赋予了巨大的保护。这 肝保护与抑制固醇调节元件结合蛋白-1有关 （SREBP-1）激活和降低脂肪生成基因表达。总体目标 提案以确定特定脂肪生成基因表达下降如何促进 TTC39B缺乏的肝保护作用。 Hsieh博士将在 饮食引起的脂肪性肝炎的小鼠模型，表现出许多组织学特征 在人NASH中观察到，包括炎性细胞浸润和纤维化。在第一个目标中 TTC39B对SREBP-1激活的影响将进一步探索，以了解 NAFLD的早期发病机理。第一个Subaim将确定SREBP-1是否 TTC39B缺乏症中的失活正在推动防止脂肪性肝炎的保护 将研究磷脂代谢在这种失活中的作用。第二个目标 探索TTC39B缺乏症中磷脂酸信号传导的抑制是否会阻止 NAFLD向更严重的非酒精性脂肪性肝炎（NASH）的进展。 Hsieh博士 科学研究和职业发展将得到她的成员的进一步支持 顾问委员会，包括Muredach Reilly博士，Robert Schwabe博士和Richard博士 Deckelbaum。指导和咨询团队将有助于扩大Hsieh博士的方法 科学假设检验并确保她成为独立研究者的成功。