Genetic basis of liver repopulation

肝脏再生的遗传基础

• 批准号: 8949786
• 负责人: Kirk J Wangensteen
• 金额: $ 15.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949786
• 关键词: Adult; Advisory Committees; Affect; Alcohols; Amino Acids; Anti-Tumor Necrosis Factor Therapy; Attenuated; Binding Sites; Body Weight decreased; Candidate Disease Gene; Cell Death; Cell Surface Receptors; ChIP-seq; Congenital Disorders; DNA Binding; Development; Drug Exposure; Drug Targeting; Environment; Exposure to; Funding; Gastroenterology; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Genetic screening method; Genomic DNA; Goals; Hepatocyte; Hepatology; Human; Inflammation; Inflammatory; Injury; Injury to Liver; Investigation; Journals; Laboratories; Lead; Libraries; Liver; Liver Regeneration; Liver diseases; Location; Manuscripts; Mediating; Mentorship; Modeling; Molecular; Mus; Natural regeneration; Partial Hepatectomy; Pathway interactions; Pennsylvania; Pharmaceutical Preparations; Physicians; Play; Process; Receptors, Tumor Necrosis Factor, Type II; Research Personnel; Rodent; Role; Scientist; Signal Pathway; Signal Transduction; Societies; Tertiary Protein Structure; Therapeutic; Time; Toxin; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Universities; Viral hepatitis; Virus Diseases; abstracting; base; cell injury; clinically significant; design; drug candidate; forkhead protein; genome-wide; human TNFRSF1A protein; improved; inflammatory modulation; inhibitor/antagonist; injured; innovation; insight; interest; liver injury; meetings; mortality; novel; overexpression; programs; promoter; public health relevance; research study; response; transcription factor; tumor necrosis factor alpha receptor

 DESCRIPTION (provided by applicant): A better understanding of how the liver regenerates in response to toxic injuries, such as from drug exposure or viral infection, will lead to new treatments with an immense impact on liver disease. We have developed an innovative genetic screen to identify and rank - for the first time - key regulators of liver repopulation following toxic injury. We have discovered two exceptional associations among the >40 genes: (1) Foxa3, a transcription factor that is known to be important for liver development, is one of the strongest promoters of liver repopulation, and (2) Tumor Necrosis Factor Receptor 1 (TNFR1), important for signaling of inflammation in hepatocytes and previously thought to help initiate liver regeneration, was found to be the most significant suppressor of repopulation among all the genes tested. The hypothesis of this proposal is that Foxa3 and TNFR1 play critical roles in regulating liver regeneration. We propose the following Specific Aims: Specific Aim 1: To investigate the mechanisms underlying Foxa3-mediated promotion of liver repopulation. Specific Aim 2: To assess whether TNFR1 deletion and targeted anti-TNF therapy can promote liver repopulation. The experimental approach outlined here is designed to carefully dissect the roles of Foxa3 and TNFR1 in regulating liver regeneration, and to assess the clinical significance of these findings. We will identify how genetic deletion of Foxa3 and TNFR1 affects liver repopulation. We will characterize the protein domains and the genomic DNA binding sites of Foxa3 that are necessary to enhance repopulation. Finally, we will assess the signaling pathway for TNFR1 that inhibits repopulation and whether drugs targeting TNFR1 inflammatory signaling can improve liver repopulation. This proposal also outlines my 5-year plan to continue to develop as a physician-scientist in Gastroenterology, with the goal of becoming an independent principle investigator. As a clinician, I plan to focus in hepatology, and with a sub-focus on adults with congenital disorders of the liver. As a scientist, I will continue to flourish under th mentorship of Dr. Kaestner, and will continue to engage with the lab in regular meetings and journal clubs. I will meet semi-annually with an advisory committee consisting of senior physician-scientists in gastroenterology, Drs. Ben Stanger and Michael Pack. I plan to submit manuscripts to high-impact journals and to obtain funding from the NIH and from GI societies. The Gastroenterology Division at the University of Pennsylvania has a long track record of preparing successful physician-scientists and is an ideal environment for my maturation toward independent laboratory investigation.

 描述（由申请人提供）：更好地了解肝脏如何响应毒性损伤（例如药物暴露或病毒感染）而再生，将带来对肝病产生巨大影响的新疗法。我们开发了一种创新的基因筛查，首次对中毒性损伤后肝脏再生的关键调节因子进行识别和排序。我们发现了超过 40 个基因之间的两个特殊关联：(1) Foxa3，一种已知对肝脏发育非常重要的转录因子，是最强的转录因子之一。 (2) 肿瘤坏死因子受体 1 (TNFR1)，对肝细胞炎症信号非常重要，之前被认为有助于启动肝脏再生，被发现是所有测试基因中最重要的再增殖抑制因子。该提议的假设是 Foxa3 和 TNFR1 在调节肝再生中发挥关键作用。我们提出以下具体目标： 具体目标 1：研究 Foxa3 介导的肝脏再生促进机制。具体目标 2：评估 TNFR1 缺失和靶向抗 TNF 治疗是否可以促进肝脏再生。这里概述的实验方法旨在仔细剖析 Foxa3 和 TNFR1 在调节肝再生中的作用，并评估这些发现的临床意义。我们将确定 Foxa3 和 TNFR1 的基因缺失如何影响肝脏重建。我们将表征 Foxa3 的蛋白质结构域和基因组 DNA 结合位点，这些对于增强再增殖是必需的。最后，我们将评估 TNFR1 抑制再增殖的信号通路，以及针对 TNFR1 炎症信号传导的药物是否可以改善肝脏再增殖。该提案还概述了我作为胃肠病学医师科学家继续发展的五年计划，目标是成为一名独立的首席研究员。作为一名临床医生，我计划专注于肝病学，并重点关注患有先天性肝脏疾病的成人。作为一名科学家，我将在凯斯特纳博士的指导下继续蓬勃发展，并将继续通过定期会议和期刊俱乐部与实验室互动。我将每半年与一个由胃肠病学高级医师科学家、Drs. 组成的咨询委员会会面。本·斯坦格和迈克尔·帕克。我计划向高影响力期刊提交手稿，并从 NIH 和 GI 协会获得资金。宾夕法尼亚大学胃肠病学部门在培养成功的医师科学家方面拥有悠久的历史，是我走向独立实验室研究成熟的理想环境。