Dissecting stromal-epithelial interactions in the adult exocrine pancreas

描述（由申请人提供）： 本提案描述了一个为期五年的综合指导培训计划，以发展胰腺病学的学术基础科学研究事业。主要研究者已经完成了胃肠病学的临床研究，并寻求建立在他现有的研究经验和技能，成为一个成功的独立研究者在研究领域，需要额外的多学科培训。 研究者将获得一套独特的技能，以研究胰腺疾病中的基质-上皮相互作用。虽然被认为是重要的，我们了解成人胰腺疾病，如胰腺炎和癌前病变，很少有人知道间质和上皮细胞之间的串扰。为了剖析这一现象，研究者将通过正式的课程整合胰腺发育和干细胞生物学的概念，掌握相关的技术技能，并由这些领域的专家指导。调查员已经确定了两名著名的医生-科学家，以帮助获得这种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医生兼科学家，是胰腺发育和使用遗传小鼠模型研究发育信号通路的权威。Anil Rustgi博士是宾夕法尼亚大学胃肠病学主任，他以将发展原则应用于理解包括癌症在内的胃肠道疾病而闻名。此外，还成立了一个由受人尊敬的NIH资助的研究人员组成的咨询委员会，以提供科学和专业指导。 在这些合格人员的指导下，将建立一个解剖成人胰腺基质-上皮相互作用的研究计划。在过去的两年中，研究者开发了技术[原文如此]来研究来自胰腺疾病新小鼠模型的原代胰腺肌成纤维细胞和上皮细胞。使用这些方法，肌成纤维细胞，胰腺基质的主要组成部分，被证明有利于胰腺上皮细胞在共培养的去分化和增殖。相反，上皮细胞在共培养的肌成纤维细胞中产生表型变化。Notch和Hedgehog通路的药理学抑制增强了这些作用。由于已知这些抑制剂会影响其他途径，因此拟议的实验将确定Notch和Hedgehog信号传导在体外和体内使用新型遗传方法介导基质-上皮相互作用中的性质和贡献。 宾夕法尼亚大学的研究者可利用的综合资源，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本补助金培训部分的环境，执行拟议的研究计划，并在胰腺病学的调查，将作为一个跳板，为研究者的职业生涯作为一个独立的医生，科学家的独特线的发展。

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.