Hepatoprotective Mechanisms of TTC39B Deficiency

TTC39B 缺陷的保肝机制

基本信息

批准号：
10153765
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
项目类别：
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/10153765
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/antagonist 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

项目摘要

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 缺乏症的保肝机制 PI：Hsieh, Joanne 项目概要/摘要此 K01 应用程序旨在提供过渡所需的资源和培训 Joanne Hsieh 博士在肝病脂质代谢领域完全独立。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，该系表现出了对初级教师的承诺指导。她将得到 Alan Tall 博士的指导，他是一位杰出的研究员脂蛋白代谢和动脉粥样硬化。与儿科 Joel Lavine 医生合影作为她的共同导师，谢博士将把她的重点转向非酒精性脂肪肝疾病（非酒精性脂肪肝）。 Lavine 博士在成人和儿童 NAFLD 方面拥有丰富的临床研究记录，并将成为谢博士将转化目标纳入培训的一部分以生物力学为重点的研究。谢博士将继续她的小说《TTC39B》的研究人类 GWAS 中与 HDL-胆固醇显着相关的基因。谢博士最近展示 TTC39B 的缺陷可以显着保护小鼠免受脂肪性肝炎的侵害。这保肝作用与抑制甾醇调节元件结合蛋白-1有关 (SREBP-1) 激活并降低脂肪生成基因表达。该项目的总体目标是确定特定脂肪生成基因的表达减少如何促进 TTC39B 缺陷的保肝作用。谢博士将在一个饮食诱导的脂肪性肝炎小鼠模型表现出许多组织学特征在人类 NASH 中观察到，包括炎症细胞浸润和纤维化。在第一个目标中， TTC39B 对 SREBP-1 激活的影响将进一步从机制上进行探索以了解 NAFLD 的早期发病机制。第一个子目标将确定 SREBP-1 是否 TTC39B 缺陷的失活正在推动对脂肪性肝炎的保护，而第二个将研究磷脂代谢在这种失活中的作用。第二个目标将探讨 TTC39B 缺陷中磷脂酸信号传导的抑制是否可以预防 NAFLD 进展为更严重的非酒精性脂肪性肝炎 (NASH)。谢博士的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 博士德克尔鲍姆。指导和咨询团队将帮助拓宽谢博士的方法科学假设检验并确保她作为独立调查员的成功。