Lung Myofibroblast De-Differentiation and Fibrosis Resolution Depend on cAMP-mediated Inhibition of HuR.

项目概要/摘要： 该提案描述了一个五年的研究和职业发展计划，旨在支持申请人的 进展到一个独立的医生，科学家调查机制肺肌成纤维细胞（MF）去， 分化/清除和肺纤维化消退。 研究计划：特发性肺纤维化（IPF）是最致命的纤维化肺病，影响数百万人， 全球范围内的个体，治疗选择有限，无法逆转已建立的纤维化。MF是 创伤修复后持续存在的IPF最终效应细胞-其凋亡的结果 阻力-导致进行性肺瘢痕和僵硬，扭曲组织结构和损害气体 交易所肺MFs的清除-通过其表型去分化和细胞凋亡的恢复 敏感性-有可能解决纤维化。申请人已经发现肺MF去分化 可以通过不同的过渡表型进行，mRNA的转录后调节对于 这个过程在这个建议中，他将研究内源性抗纤维化制动环腺苷的作用 一磷酸腺苷（cAMP）及其对主要转录后调节因子人抗原R（HuR）的调节 在MF去分化和纤维化消退中。 申请人和培训计划：申请人拥有医学博士学位，并已完成内部临床培训 医学，肺和重症监护医学。在他的奖学金和先前的研究工作，他已经 获得了成纤维细胞生物学体外系统和基本实验室技术的经验。作为他职业生涯的一部分 发展，申请人将参加旨在发展新知识的指导研究， 精通RNA生物学、CRISPR/Cas9技术、免疫荧光显微镜、生物信息学， 新型转基因小鼠用于肺纤维化的体内建模和研究的用途。收购这些新 技能和经验将大大有助于他发展成为一个独立的调查员， MFs可以去分化和清除的机制，使促进纤维化的策略成为可能 分辨率这些领域的培训将在他经验丰富的指导团队的指导下进行， 通过参加研讨会、实验室会议、课程作业、讲习班和国家会议。他还将 接受撰写资助和负责任地开展研究的培训。杰出的机构研究 环境为申请人提供了与RNA研究人员互动的丰富机会， 分子生物学，肺和肺外纤维化，以及与基础和转化科学家。 先进的成像，RNA测序和转基因动物建模的现有设施将被利用。 因此，这一应用程序将使一个受过良好训练和承诺的初级调查员， 职业生涯中的细胞和分子机制的调查，可以转化为解决 已证实的肺纤维化-该领域研究的圣杯和巨大的未满足的临床需求。

Project Summary/Abstract: This proposal describes a five-year research and career development plan intended to support the applicant’s progression to an independent physician-scientist investigating mechanisms of lung myofibroblast (MF) de- differentiation/clearance and pulmonary fibrosis resolution. Research Plan: Idiopathic pulmonary fibrosis (IPF) is the deadliest fibrotic lung disease, affecting millions of individuals worldwide, with limited treatment options that fail to reverse established fibrosis. MFs are the ultimate effector cells of IPF whose persistence following wound repair – a consequence of their apoptosis resistance – leads to progressive lung scarring and stiffness, distorting tissue architecture and impairing gas exchange. Clearance of lung MFs – through their phenotypic de-differentiation and restoration of apoptosis sensitivity – has the potential to resolve fibrosis. The applicant has discovered that lung MF de-differentiation can proceed via distinct transitional phenotypes and that post-transcriptional regulation of mRNAs is crucial to this process. In this proposal, he will investigate the role of the endogenous anti-fibrotic brake cyclic adenosine monophosphate (cAMP) and its regulation of the master post-transcriptional regulator human antigen R (HuR) in MF de-differentiation and fibrosis resolution. Applicant and Training Plan: The applicant holds an MD degree and has completed clinical training in Internal Medicine, Pulmonary, and Critical Care Medicine. During his fellowship and prior research endeavors, he has gained experience with in vitro systems and basic lab techniques in fibroblast biology. As part of his career development, the applicant will participate in mentored research designed to develop new knowledge and proficiency in RNA biology, CRISPR/Cas9 techniques, immunofluorescence microscopy, bioinformatics, and use of novel transgenic mice for in vivo modeling and investigation of pulmonary fibrosis. Acquiring these new skills and experiences will greatly facilitate his development into an independent investigator studying the mechanisms by which MFs can be de-differentiated and cleared, enabling strategies to promote fibrosis resolution. Training in these areas will be acquired under the guidance of his experienced mentoring team, and through participation in seminars, lab meetings, coursework, workshops, and national meetings. He will also receive training in grant writing and responsible conduct of research. The outstanding institutional research environment provides the applicant abundant opportunities for interaction with investigators in RNA and molecular biology, pulmonary and extra-pulmonary fibrosis, as well as with basic and translational scientists. Available facilities for advanced imaging, RNA sequencing, and transgenic animal modeling will be utilized. This application will thus enable a well-trained and committed junior investigator to develop an independent career in the investigation of cellular and molecular mechanisms that can be translated into the resolution of established pulmonary fibrosis – the holy grail of research in this field and an enormous unmet clinical need.