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（由申请人提供）：更好地了解肝脏如何响应药物暴露或病毒感染等毒性损伤而再生，将带来对肝脏疾病产生巨大影响的新疗法。首次对毒性损伤后肝脏再生的关键调节因子进行鉴定和排名我们发现了超过 40 个基因之间的两个特殊关联：(1) Foxa3，一种已知对肝脏发育很重要的转录因子。中的一个最强 (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 介导的促进作用的机制。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。此处概述的实验方法旨在仔细剖析 Foxa3 和 TNFR1 在调节肝脏再生中的作用，并评估临床效果。我们将确定 Foxa3 和 TNFR1 的基因缺失如何影响肝脏重建。我们将描述增强重建所必需的 Foxa3 的蛋白质结构域和基因组 DNA 结合位点。最后，我们将评估抑制再增殖的 TNFR1 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 5 年计划，目标是作为一名独立的首席研究员，我计划专注于肝病学，并重点研究患有先天性肝脏疾病的成人。作为一名科学家，我将继续在该领域蓬勃发展。 Kaestner 博士将继续与实验室进行定期会议和期刊俱乐部的交流，我将每半年与一个由胃肠病学高级医师科学家 Ben Stanger 博士和导师 Michael Pack I 组成的咨询委员会会面。计划向高影响力期刊提交稿件，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记录，对我来说是一个理想的环境。走向独立实验室研究的成熟。