The Role Wnt Signaling in Biliary Homeostasis and Disease

Wnt 信号转导在胆道稳态和疾病中的作用

• 批准号: 10432137
• 负责人: Vikas Gupta
• 金额: $ 16.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432137
• 关键词: AGTR2 gene; Adult; Affect; Animals; Biliary; Biological Assay; Cancerous; Carcinoma; Cell Communication; Cells; Cholangiocarcinoma; Cholestasis; Clinical; Columnar Epithelium; Complex; Data; Development Plans; Disease; Duct (organ) structure; Educational workshop; Epithelial; Epithelial Cells; Fibrosis; Functional disorder; Funding; Generations; Genetic; Goals; Grant; Hepatobiliary; Hepatocyte; Homeostasis; Human; In Situ; In Situ Hybridization; Inflammation Process; Injury; Intestines; Knowledge; Ligation; Maintenance; Maps; Mechanics; Medical; Memorial Sloan-Kettering Cancer Center; Mentors; Mesenchymal; Mesenchyme; Mus; Myofibroblast; Organ; Pathology; Pathway interactions; Physicians; Play; Population; Process; Program Development; Publications; Publishing; Research; Research Personnel; Research Proposals; Respiratory System; Role; Scientist; Sclerosing Cholangitis; Signal Transduction; Skin; Sorting - Cell Movement; Source; Structure; Technical Expertise; Therapeutic; TimeLine; Tissues; Toxin; Training; Training Programs; United States National Institutes of Health; Universities; WNT Signaling Pathway; Western Blotting; Work; Writing; autocrine; bile duct; biliary tract; career development; cholangiocyte; effective therapy; experimental study; in vivo; liver transplantation; loss of function; medical schools; multimodality; paracrine; prevent; primary sclerosing cholangitis; research and development; respiratory; response to injury; single-cell RNA sequencing; smoothened signaling pathway; stem; stem cells; symposium; transcription factor; transcriptome; transcriptome sequencing

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.

项目概要/摘要 该提案包括 Vikas Gupta 博士的五年研究和职业发展计划，以实现 作为肝胆疾病研究者的独立性。 Gupta 博士是一位医学科学家，完成了 他在 NIH 资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 开发活动将在三机构区域内的康奈尔大学威尔医学院进行 包括纪念斯隆凯特琳癌症中心和洛克菲勒大学。为了促进他的目标 古普塔博士将领导自己的独立研究小组，从事多项职业发展 活动涵盖获取新技术技能、教学课程、资助写作、研讨会、 指导、会议演讲以及专门指导委员会的支持。他制定了一个 除了后续出版物和获取资金的时间安排外，还明确了这些活动的时间表。这 本提案中描述的研究和职业发展计划的结合将使候选人能够 成熟为一名成功且独立的医师科学家。该提案的研究重点是 了解胆周间质源性 Wnt 在控制柱状胆管细胞中的作用 稳态和疾病期间的增殖和细胞身份/分化，这是建立在先前的基础上的 古普塔博士发表的研究成果。 原发性硬化性胆管炎、胆管癌等大胆管疾病很少见。 肝移植以外的治疗选择。我们的差距凸显了进展的缺乏 了解大胆管病理生理学。管腔内有柱状胆管细胞上皮 大胆管，而大胆管又被一群胆周间充质细胞（PMC）包围， 是Gli1+。这两个细胞群如何相互交流对于理解如何进行交流至关重要 胆管系统出现纤维化和癌性疾病。本研究的主要假设是PMCs形成 通过旁分泌调节胆管细胞增殖和细胞识别的 Wnt 分泌生态位 通过自分泌效应影响并调节其自身的细胞特性。本研究计划的第一个目标 的目的是定义 PMC 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 控制增殖和细胞身份的机制 体内平衡。第三个目标是剖析 PMC 衍生的 Wnt 在胆道术后增殖和纤维化中的作用。 受伤。本提案中提出的实验将为人们提供新的机制理解 Wnt 信号在胆道病理生理学中的作用。这项工作将对我们如何理解产生广泛的影响 胆道稳态以及如何剖析胆管树的纤维化和癌性疾病。