Dissecting stromal-epithelial interactions in the adult exocrine pancreas

描述(由申请人提供)： 这项建议描述了一项为期五年的综合导师培训计划，旨在发展胰腺病学的学术基础科学研究生涯。首席研究员已经完成了胃肠病学的临床研究，并试图利用他现有的研究经验和技能，在需要额外的多学科培训的研究领域成为一名成功的独立研究员。 调查者将获得一套独特的技能来研究胰腺疾病中间质-上皮之间的相互作用。虽然公认对我们理解成人胰腺疾病，如胰腺炎和胰腺癌很重要，但对基质和上皮之间的串扰知之甚少。为了剖析这一现象，研究人员将通过正式的课程作业、掌握相关的技术技能以及这些领域的专家的指导，将胰腺发育和干细胞生物学的概念整合起来。调查员已经确定了两位著名的内科科学家来帮助获得这方面的专业知识和他的专业发展。本·斯坦格博士是一位训练有素的内科科学家，是胰腺发育和利用遗传小鼠模型研究发育信号通路方面的权威。宾夕法尼亚大学胃肠病学主任阿尼尔·鲁斯特吉博士以将发育原理应用于了解包括癌症在内的胃肠道疾病而闻名。此外，一个由受人尊敬的NIH资助的调查人员组成的咨询委员会已经成立，以提供科学和专业指导。 在这些合格个体的指导下，将建立一个解剖成人胰腺间质-上皮相互作用的研究计划。在过去的两年里，研究人员开发了技术[原创技术]来研究胰腺疾病新模型小鼠的原代胰腺肌成纤维细胞和上皮细胞。利用这些方法，胰腺间质的主要成分肌成纤维细胞在共培养中被证明有助于胰腺上皮细胞的去分化和增殖。相反，在共培养的肌成纤维细胞中，上皮细胞产生表型变化。对Notch和Hedgehog通路的药物抑制增强了这些效应。由于这些抑制剂已知影响其他途径，拟议的实验将确定Notch和Hedgehog信号在体外和体内使用新的遗传方法介导基质-上皮相互作用中的性质和贡献。 宾夕法尼亚大学为研究人员提供的综合资源，包括NIDDK资助的消化和肝病分子研究中心，将提供一个有利于完成这项拨款的培训部分的环境，执行拟议的研究计划，并开发一条独特的胰腺学研究路线，作为研究人员作为独立内科科学家的职业生涯的跳板。 公共卫生相关性： 胰腺炎和泛宁是胰腺癌的先兆，是胰腺中最常见和最致命的两种疾病，目前还没有好的治疗方法。我们的研究将检查胰腺中涉及这些疾病的两种不同类型的上皮细胞和间质细胞是如何相互作用的。通过了解这些细胞是如何合作的，我们希望为开发诊断和治疗这些疾病的新方法提供新的线索。

DESCRIPTION (provided by applicant): This proposal describes a five year integrated mentored training program for the development of an academic basic science research career in pancreatology. The Principal Investigator has completed a clinical fellowship in Gastroenterology and seeks to build on his existing research experience and skills to become a successful independent investigator in an area of research that requires additional multi-disciplinary training. The Investigator will acquire a unique skill set to study stromal-epithelial interactions in pancreatic disease. While recognized to be important to our understanding of adult pancreatic diseases, such as pancreatitis and preneoplasia, little is known regarding crosstalk between the stroma and epithelium. To dissect this phenomenon, the Investigator will integrate concepts from pancreas development and stem cell biology through formal coursework, mastering of relevent [sic] techincal [sic] skills, and mentorship by experts in these fields. The Investigator has identified two renowned physician-scientists to aid in the acquisition of this expertise and in his professional development. Dr. Ben Stanger, a well-trained physician-scientist, is an authority in pancreas development and the study of developmental signaling pathways using genetic mouse models. Dr. Anil Rustgi, Chief of Gastroenterology at the University of Pennsylvania, is renowned for his work in the application of developmental principles to the understanding of gastrointestinal diseases, including cancer. Additionally, an advisory committee comprised of respected NIH-funded investigators has been formed to provide scientific and professional guidance. With the mentorship of these qualified individuals, a research program dissecting stromal-epithelial interactions in the adult pancreas will be established. For the past two years, the Investigator has developed techinques [sic] to study primary pancreatic myofibroblasts and epithelial cells from novel mouse models of pancreatic disease. Using these methods, myofibroblasts, a major component of the pancreatic stroma, were shown to facilitate the dedifferentiation and proliferation of pancreas epithelial cells in co-culture. Conversely, epithelial cells produced phenotypic [sic] changes in co-cultured myofibroblasts. Pharmacologic inhibition of the Notch and Hedgehog pathways augmented these effects. Since these inhibitors are known to affect other pathways, the proposed experiments will determine the nature and contribution of Notch and Hedgehog signaling in mediating stromal-epithelial interactions using novel genetic approaches in vitro and in vivo. The combined resources available to the Investigator at the University of Pennsylvania, including the NIDDK-funded Center for Molecular Studies in Digestive and Liver Diseases, will provide an environment conducive to the completion of the training component of this grant, execution of the proposed research program, and development of a unique line of investigation in pancreatology that will serve as a springboard for the Investigator's career as an independent physician-scientist. PUBLIC HEALTH RELEVANCE: Pancreatitis and PanIN, the precursor to pancreatic cancer, are two of the most prevalent and deadly diseases of the pancreas for which no good treatments are available. Our studies will examine how epithelial and stromal cells, the two different cell types in the pancreas involved in these diseases, interact. Through understanding how these cells cooperate, we hope to shed new light on the development of new ways of diagnosing and treating these diseases.