The Role Wnt Signaling in Biliary Homeostasis and Disease

项目摘要/摘要 该提案包括一项为期五年的研究和职业发展计划，供维卡斯·古普塔博士实现 独立从事肝胆疾病的研究。古普塔博士是一位内科科学家，他完成了 他在NIH赞助的医学科学家培训计划中接受了培训。拟议的研究和职业 发展活动将在康奈尔大学威尔医学院三个机构区域内进行 包括纪念斯隆·凯特琳癌症中心和洛克菲勒大学。以促进他的目标 古普塔博士领导着自己的独立研究小组，将从事一系列职业发展 活动范围包括获得新的技术技能、教学课程、赠款撰写、讲习班、 指导、会议演示和来自专门指导委员会的支持。他已经制定了一项 这些活动的明确时间表，以及后续出版物的时间安排和资金筹措。这个 这份建议书中描述的研究和职业发展计划的结合将使应聘者能够 成长为一名成功的、独立的内科科学家。该提案的研究重点是 胆管周围间充质来源的WNTs在控制柱状胆管细胞中的作用 在动态平衡和疾病期间的增殖和细胞识别/分化，这是建立在以前的 古普塔博士发表的研究。 大胆管疾病，如原发性硬化性胆管炎和胆管癌，几乎没有什么 肝移植以外的治疗选择。我们的差距突显了缺乏进步 对大胆管病理生理学的认识。管腔内排列着柱状胆管上皮细胞。 大胆管，胆管周围有大量间充质细胞(PMC)， 是Gli1+。这两个细胞群体如何相互沟通对于理解 胆管树的纤维化和癌性疾病就会出现。这项研究的主要假设是，私营军事公司形成 一个通过旁分泌调节胆管细胞增殖和细胞鉴定的Wnt分泌区 通过自分泌效应影响和调节自身的细胞身份。这项研究提案的第一个目的是 目的是明确PMCs和柱状胆管细胞的WNT如何随损伤而变化。第二个目标是 了解PMC衍生的WNTs在过程中控制增殖和细胞特性的机制 动态平衡。第三个目的是分析PMC来源的WNTs在胆道术后增殖和纤维化中的作用。 受伤。这项提案中提出的实验将提供对 Wnt信号在胆道病理生理中的作用这项工作将对我们如何理解 胆道动态平衡和如何解剖胆管树的纤维化和癌性疾病。

Project Summary/Abstract This proposal comprises a five year research and career development program for Dr. Vikas Gupta to achieve independence as an investigator in hepatobiliary diseases. Dr. Gupta is a physician-scientist who completed his training in an NIH-sponsored Medical Scientist Training Program. The proposed research and career development activities will occur at Weill Medical College of Cornell University within the Tri-Institutional region encompassing Memorial Sloan Kettering Cancer Center and Rockefeller University. To facilitate his goal of leading his own independent research group, Dr. Gupta will engage in a number of career development activities spanning the acquisition of new technical skills, didactic coursework, grant writing, workshops, mentoring, conference presentations, and support from a dedicated mentoring committee. He has laid out a clear timeline for these activities in addition to timing of subsequent publications and acquisition of funding. The combination of research and career development plans described in this proposal will allow the candidate to mature into a successful and independent physician-scientist. The research focus of the proposal is upon understanding the role of peribiliary mesenchymal derived Wnts in controlling columnar cholangiocyte proliferation and cellular identity/differentiation during homeostasis and disease, which builds upon previously published research by Dr. Gupta. Diseases of the large bile ducts such as primary sclerosing cholangitis and cholangiocarcinoma have had little therapeutic options outside of liver transplantation. The lack of advance is underscored by gaps in our understanding of large bile duct pathophysiology. An epithelium of columnar cholangiocytes lines the lumen of large bile ducts, which in turn are surrounded by a population of peribiliary mesenchymal cells (PMCs) which are Gli1+. How these two cell populations communicate with one another is crucial to understanding how fibrosing and cancerous diseases of the biliary tree arise. The main hypothesis of this study is that PMCs form a Wnt secreting niche that regulates the proliferation and cellular identify of cholangiocytes through paracrine effects and regulates their own cellular identity through autocrine effects. The first aim of this research proposal is to define how Wnts from PMCs and columnar cholangiocytes change with injury. The second aim is to understand the mechanism through which PMC derived Wnts controls proliferation and cellular identity during homeostasis. The third aim is dissect the role of PMC derived Wnts for proliferation and fibrosis after biliary injury. The experiments that are presented in this proposal will provide a new mechanistic understanding of the role of Wnt signaling in biliary pathophysiology. This work will have broad implications for how we understand biliary homeostasis and how to dissect fibrosing and cancerous diseases of the biliary tree.