Genetic basis of liver repopulation

肝脏再生的遗传基础

• 批准号: 9107858
• 负责人: Kirk J Wangensteen
• 金额: $ 15.53万
• 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/9107858
• 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; Drug Exposure; Drug Targeting; Environment; Exposure to; Funding; Gastroenterology; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Genetic screening method; Genomic DNA; Goals; Health; 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; Pharmacotherapy; Physicians; Play; Process; Research Personnel; Rodent; Role; Scientist; Signal Pathway; Signal Transduction; Societies; TNF gene; TNFRSF1A gene; Tertiary Protein Structure; Therapeutic; Time; Toxin; United States National Institutes of Health; Universities; Viral hepatitis; Virus Diseases; abstracting; base; cell injury; clinically significant; design; forkhead protein; genome-wide; improved; inflammatory modulation; injured; innovation; insight; interest; liver development; liver injury; meetings; mortality; novel; novel therapeutics; overexpression; programs; promoter; research study; response; transcription factor; tumor necrosis factor-alpha inhibitor

 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（如药物暴露或病毒感染）而再生，将导致对肝脏疾病产生巨大影响的新治疗方法。我们已经开发出一种创新的遗传筛选，以识别和排名-第一次-中毒损伤后肝脏再生的关键调节因子。我们在超过40个基因中发现了两个特殊的关联：（1）Foxa 3，一种已知对肝脏发育很重要的转录因子，是最强的关联之一。 发现（1）肿瘤坏死因子受体1（TNFR 1）是肝细胞再生的重要启动子，（2）肿瘤坏死因子受体1（TNFR 1）对肝细胞中炎症的信号传导很重要，以前认为有助于启动肝再生，在所有测试的基因中发现它是最重要的再生抑制因子。该建议的假设是Foxa 3和TNFR 1在调节肝再生中起关键作用。我们提出以下具体目的：具体目的1：研究Foxa 3介导的促进肝脏再生的机制。具体目标2：评估TNFR 1缺失和靶向抗TNF治疗是否可以促进肝脏再生。本文概述的实验方法旨在仔细剖析Foxa 3和TNFR 1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Foxa 3和TNFR 1基因缺失如何影响肝脏再生。我们将表征Foxa 3的蛋白质结构域和基因组DNA结合位点，这些位点是增强再增殖所必需的。最后，我们将评估TNFR 1抑制再生的信号通路，以及靶向TNFR 1炎症信号的药物是否可以改善肝脏再生。该提案还概述了我的5年计划，以继续发展为胃肠病学的医生科学家，目标是成为独立的主要研究者。作为一名临床医生，我计划专注于肝病学，并专注于患有先天性肝脏疾病的成年人。作为一名科学家，我将继续在Kaestner博士的指导下蓬勃发展，并将继续参加实验室的定期会议和期刊俱乐部。我将每半年与一个由胃肠病学高级医生科学家组成的咨询委员会会面，Ben Stanger博士和Michael Pack博士。我计划向高影响力的期刊投稿，并从NIH和GI协会获得资助。宾夕法尼亚大学的胃肠病学分部在培养成功的医生科学家方面有着悠久的历史，是我走向独立实验室研究的理想环境。