Alpha3Beta Integrin Function in Epithelial-Mesenchymal Transition and Fibrosis

描述（由申请人提供）： 本申请的目的是扩大本申请人的科学技能，最终产生一个独立的研究者能够终身的临床相关的科学贡献。下面描述的项目集中于α 3 β 1整合素在上皮-间质转化（EMT）和肺纤维化中的作用。该申请人作为住院医师和临床研究员已经花了几年时间研究肺纤维化。在这些年里，申请人掌握了几项基本的研究技术。虽然下文描述的研究将允许进一步改进和获得几种新技术，但我们相信，成为一名独立研究者的追求需要在批判性思维、创新、科学写作、指导和建立合作的能力方面进行大量的概念培训。因此，职业发展计划将包括重点课程、参加一些科学会议以及与其他调查人员合作。在过去的两年中，我们一直在探索α 3 β 1调节TGF β 1的机制，TGF β 1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。第一种是强力霉素诱导的肺泡上皮细胞（AEC）特异性α 3 β 1缺失。第二个系统涉及多西环素诱导的，AEC特异性和永久性表达的报告基因，使我们能够跟踪这些细胞的命运，因为它们可能分化成间充质细胞。这两种鼠标都已经可用，并且系统已经通过多种技术验证。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证明AEC向间充质细胞的转化，并支持alpha 3 β 1在调节这一过程中的关键作用。在此奖项期间的科学目标将是探索a3 β 1在AEC中的功能，确定调节EMT的因素， 确定alpah 3 β 1和EMT在肺纤维化动物模型中的重要性。尽管多年的研究，肺纤维化仍然是一个毁灭性的问题，没有良好的治疗。随着对这一相对未探索的途径的更深入了解，纤维化发病机制的新范式可能会出现，并可能产生新的和更有效的治疗方法。 (End摘要）

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)