Alpha3Beta Integrin Function in Epithelial-Mesenchymal Transition and Fibrosis

描述(由申请人提供)： 这项申请的目标是扩大申请人的科学技能，最终产生一名能够终身做出临床相关科学贡献的独立研究人员。下面介绍的项目重点是α3beta1整合素在上皮-间充质转化(EMT)和肺纤维化中的作用。这位申请者已经作为住院医生和临床研究员花了几年的时间研究肺纤维化。在这些年里，这位申请者掌握了几项基本的研究技巧。虽然下文描述的研究将允许进一步完善和获得几项新技术，但我们认为，要成为一名独立的调查员，需要在批判性思维、创新、科学写作、指导和建立合作能力方面进行大量的概念性培训。因此，职业发展计划将包括有重点的课程工作、参加一些科学会议以及与其他调查人员合作。在过去的两年里，我们一直在探索Alpha3betal调节TGFbeta1的机制，TGFbeta1是纤维化发病机制中的关键细胞因子，也是EMT的关键调节因子。我们还开发了进一步研究的工具，包括两个复合转基因小鼠系统。第一种是多西环素诱导的、肺泡上皮细胞(AEC)特异性的α3β1丢失。第二个系统涉及多西环素诱导的、AEC特异的和永久表达的报告基因，使我们能够跟踪这些细胞在潜在分化为间充质细胞时的命运。这两种鼠标都已经上市，而且这些系统已经通过多种技术进行了验证。此外，我们已经掌握了分离和培养原代AEC的技术，并已经使用这些工具来演示AEC向间充质细胞的转化，并支持α3beta1在调节这一过程中的关键作用。本次获奖期间的科学目标将是探索α3beta1在血管内皮细胞中的功能，确定调节EMT的因素，以及 目的：探讨肺间质纤维化动物模型中alpah3beta1和EMT的作用。尽管多年来的研究，肺纤维化仍然是一个毁灭性的问题，没有良好的治疗。随着对这一相对未知的途径的更多了解，纤维化发病机制的新范式可能会出现，并有可能产生新的、更有效的治疗方法。 (摘要结束)

DESCRIPTION (provided by applicant): The goal of this application is to expand upon the scientific skills of this applicant ultimately producing an independent investigator capable of a lifetime of clinically relevant scientific contributions. The project described below focuses on the role of alpha3beta1 integrin in epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. This applicant has already spent several years studying pulmonary fibrosis, both as a resident and clinical fellow. During these years, this applicant has mastered several basic research techniques. While the studies described below will allow further refinement and the gain of several new techniques, we believe that the pursuit of becoming an independent investigator involves considerable conceptual training in critical thought, innovation, scientific writing, mentoring and the ability to establish collaborations. Thus, the career development plan will include focused course work, participation in a number of scientific meetings and collaboration with other investigators. During the past two years we have been exploring the mechanism by which alpha3betal regulates TGFbeta1, a critical cytokine in the pathogenesis of fibrosis and a key regulator of EMT. We have also developed tools for further investigation, including two compound transgenic mouse systems. The first is a doxycycline-inducible, alveolar epithelial cell (AEC)-specific loss of alpha3beta1. The second system involves doxycycline-inducible, AEC-specific and permanent expression of a reporter gene, allowing us to track the fate of these cells as they potentially differentiate into mesenchymal cells. Both of these mice are already available and the systems have been verified by multiple techniques. Furthermore, we have mastered techniques at isolating and culturing primary AECs and have already used these tools to demonstrate AEC transition into mesenchymal cells and to support a critical role for alpha3beta1 in regulating this process. The scientific goals during this award period will be to explore the function of alpha3beta1 in AECs, determine the factors which regulate EMT, and to determine the importance of alpah3beta1 and EMT in animal models of pulmonary fibrosis. Despite years of research, pulmonary fibrosis remains a devastating problem without good therapy. With greater understanding into this relatively unexplored pathway, a new paradigm for the pathogenesis of fibrosis may emerge with the potential for novel and more effective therapies. (End of Abstract)