Hepatoprotective Mechanisms of TTC39B Deficiency

TTC39B缺乏症的保肝机制 项目摘要/摘要 此K01应用程序旨在为过渡提供必要的资源和培训 谢淑丽博士在肝脏疾病的脂代谢领域完全独立。这个 拟议的工作和培训将于#年在哥伦比亚大学医学中心(CUMC)进行 医学系，它已经展示了对初级教员的承诺 师徒关系。她将得到艾伦·塔尔博士的指导，他是一位杰出的研究员 脂蛋白代谢与动脉粥样硬化。与Joel Lavine医生在儿科 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性肝病 (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， 并将在谢博士为她建立翻译目标的培训中发挥不可或缺的作用 注重生物力学的研究。谢博士将继续她对小说TTC39B的研究 与人类高密度脂蛋白胆固醇显著相关的基因。谢博士最近展示了 TTC39B的这一缺陷对小鼠的脂肪性肝炎具有显著的保护作用。这 肝脏保护与抑制的类固醇调节元件结合蛋白-1有关 (SREBP-1)激活并降低造脂基因表达。该计划的总体目标 关于确定特定致脂基因表达减少如何有助于 TTC39B缺乏症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，包括炎性细胞浸润和纤维化。第一个目标是， TTC39B对SREBP-1激活的影响将从机制上进一步探讨 NAFLD的早期发病机制。第一个子目标将决定SREBP-1是否 TTC39B缺乏的失活推动了对脂肪性肝炎的保护，而第二种 将研究磷脂代谢在这种失活中的作用。第二个目标是 探讨TTC39B缺乏症中磷脂酸信号的抑制是否可以防止 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 Schwabe博士和Richard博士 德克尔鲍姆。指导和咨询团队将有助于扩大谢博士的方法 科学的假设检验，并确保她作为一名独立调查员取得成功。

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.