Hepatoprotective Mechanisms of TTC39B Deficiency

TTC 39 B缺乏的肝保护机制PI：Hsieh，Joanne 项目总结/摘要 此K 01应用程序旨在提供必要的资源和培训， 博士Joanne Hsieh在肝脏疾病的脂质代谢领域完全独立。的 拟议的工作和培训将在哥伦比亚大学医学中心（CINC）进行， 医学系，它已经表现出对初级教师的承诺， 导师制她将由艾伦·塔尔博士指导，他是一位杰出的研究人员， 脂蛋白代谢和动脉粥样硬化。儿科的乔尔·拉文医生 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。 （NAFLD）。Lavine博士在成人和儿童NAFLD的临床研究方面有着广泛的记录， 并将成为谢博士培训中不可或缺的一部分， 生物力学研究谢博士将继续她对小说《TTC 39 B》的研究。 在人类GWAS中与HDL-胆固醇显著相关的基因。谢博士最近展示了 这种TTC 39 B的缺陷在小鼠中赋予了对脂肪性肝炎的显著保护。这 肝保护作用与抑制固醇调节元件结合蛋白-1有关 （SREBP-1）活化和减少的脂肪生成基因表达。的总体目标 建议确定特定脂肪生成基因表达的减少如何有助于 TTC 39 B缺乏的肝保护作用。谢博士将以一种 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NASH中观察到的炎症性细胞浸润和纤维化。在第一个目标中， TTC 39 B对SREBP-1激活的影响将进一步从机制上探索以了解 NAFLD的早期发病机制。第一个子目标将决定SREBP-1是否 TTC 39 B缺乏症的失活正在推动对脂肪性肝炎的保护，而第二种失活则是 将研究磷脂代谢在这种失活中的作用。第二个目标将 探索TTC 39 B缺乏症中磷脂酸信号传导的抑制是否阻止了 NAFLD进展为更严重的非酒精性脂肪性肝炎（NASH）。谢医生的 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施瓦贝博士和Richard博士 戴克鲍姆指导和咨询团队将有助于扩大谢博士的方法， 科学假设测试，并确保她作为一个独立的调查员的成功。

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.