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在中毒损伤(如药物暴露或病毒感染)时再生，将导致对肝脏疾病产生巨大影响的新治疗方法。我们已经开发了一种创新的基因筛查，以识别和排名-第一次-毒性损伤后肝脏重新繁殖的关键调节因素。我们发现了&gt；40基因之间的两个特殊关联：(1)转录因子Foxa3，已知对肝脏发育很重要，是最强的关联之一 在所有测试的基因中，肿瘤坏死因子受体1(TNFR1)被发现是最显著的再增殖抑制基因。肿瘤坏死因子受体1在肝细胞炎症信号转导中起重要作用，以前被认为有助于启动肝再生。该方案的假设是，Foxa3和TNFR1在调节肝再生中起关键作用。我们提出了以下特定目标：特定目标1：研究Foxa3介导的促进肝脏再繁殖的机制。具体目的2：评估TNFR1缺失和靶向抗肿瘤坏死因子治疗是否能促进肝脏再生。本文概述的实验方法旨在仔细分析Foxa3和TNFR1在调节肝脏再生中的作用，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再繁殖。我们将鉴定Foxa3的蛋白质结构域和基因组DNA结合部位，这是促进种群繁殖所必需的。最后，我们将评估TNFR1抑制再充血的信号通路，以及针对TNFR1炎症信号的药物是否可以改善肝脏再充盈。这份提案还勾勒出了我的五年计划，即继续发展为一名胃肠病学内科科学家，目标是成为一名独立的主要研究员。作为一名临床医生，我计划专注于肝病，并将重点放在患有先天性肝脏疾病的成年人身上。作为一名科学家，我将继续在凯斯特纳博士的指导下茁壮成长，并将继续参与实验室的定期会议和期刊俱乐部。我将每半年会见一次咨询委员会，该委员会由胃肠病学资深内科科学家本·斯坦格博士和迈克尔·帕克博士组成。我计划将手稿提交给影响力较大的期刊，并从NIH和GI协会获得资金。宾夕法尼亚大学的胃肠病学部在培养成功的内科科学家方面有着长期的记录，是我走向独立实验室研究的理想环境。