Genetic basis of liver repopulation

肝脏再生的遗传基础

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：更好地了解肝脏对毒性损伤的再生，例如因药物暴露或病毒感染而导致对肝病产生影响的新治疗。我们已经开发了一个创新的遗传筛选，以识别和排名 - 首次在毒性损伤后的肝脏再生的关键调节剂。我们已经在> 40个基因中发现了两个特殊关联：（1）FOXA3是一种对肝发育很重要的转录因子，是强的。发现肝发育症的启动子和（2）肿瘤坏死因子受体1（TNFR1）对于肝细胞中炎症信号的信号很重要，并且以前被认为有助于启动肝脏再生，这是所有测试基因中最重要的重生抑制。该提议的假设是FOXA3和TNFR1在调节肝脏再生中起关键作用。我们提出以下特定目的：具体目标1：研究FOXA3介导的促进肝脏重生的机制。特定目的2：评估TNFR1缺失和靶向抗TNF疗法是否可以促进肝脏再生。此处概述的实验方法旨在仔细剖析FOXA3和TNFR1在控制肝脏再生中的作用，并评估这些发现的临床意义。我们将确定FOXA3和TNFR1的遗传缺失如何影响肝脏再生。我们将表征FOXA3的蛋白质结构域和基因组DNA结合位点，这是增强重生所必需的。最后，我们将评估TNFR1的信号传导途径，该信号通路抑制重生以及针对TNFR1炎症信号传导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，即继续发展为胃肠病学的身体科学家，目的是成为独立的原则研究者。作为临床，我计划将重点放在肝病学上，并以亚焦点对肝脏疾病的成年人。作为一名科学家，我将在Kaestner博士的心态下继续荧光，并将继续在常规会议和期刊俱乐部中与实验室互动。我将与一个咨询委员会会面，该咨询委员会由胃肠病学高级物理学家组成，博士。 Ben Stanger和Michael Pack。我计划向高影响力期刊提交手稿，并从NIH和GI社会获得资金。宾夕法尼亚大学的胃肠病学系在准备成功的身体科学家方面有着悠久的记录，这是我成熟的独立实验室调查的理想环境。