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

项目摘要/摘要： 该提案描述了一项五年研究和职业发展计划，旨在支持申请人的 成为一名独立的内科医生兼科学家，研究肺肌成纤维细胞(MF)脱纤维的机制。 分化/清除与肺纤维化消退。 研究计划：特发性肺纤维化(IPF)是最致命的纤维性肺部疾病，影响数百万人 世界各地的个人，治疗选择有限，未能逆转已建立的纤维化。MFS是 IPF的终末效应细胞在伤口修复后的持久性--其凋亡的结果 抵抗力-导致进行性肺疤痕和僵硬，扭曲组织结构和损害气体 交换。肺MFS的清除--通过其表型去分化和恢复细胞凋亡 敏感性--具有解决纤维化的潜力。申请人发现，肺间质瘤去分化 可以通过不同的过渡性表型进行，mRNAs的转录后调控对 这一过程。在这项提案中，他将研究内源性抗纤维化刹车环腺苷的作用 一磷酸(CAMP)及其对人类抗原R(HUR)主要转录后调节因子的调节 在多发性骨髓瘤去分化和纤维化消退方面。 申请人及培训计划：申请人拥有医学博士学位，并已完成内科临床培训 医学、肺和危重病护理医学。在他担任研究员期间和之前的研究工作中，他 在成纤维细胞生物学的体外系统和基本实验室技术方面获得经验。作为他职业生涯的一部分 发展，申请人将参加指导研究，旨在开发新的知识和 精通RNA生物学、CRISPR/CAS9技术、免疫荧光显微镜、生物信息学和 利用新型转基因小鼠进行肺纤维化的活体建模和研究。获得这些新的 技能和经验将极大地促进他发展成为一名研究 去分化和清除MFS的机制，使促进纤维化的战略成为可能 决议。这些领域的培训将在其经验丰富的指导团队的指导下进行，以及 通过参加研讨会、实验室会议、课程作业、研讨会和全国会议。他还将 接受拨款撰写和负责任的研究指导方面的培训。杰出的院校研究 环境为申请者提供了大量与RNA和RNA研究人员互动的机会 分子生物学、肺和肺外纤维化，以及基础科学家和翻译科学家。 将利用先进的成像、RNA测序和转基因动物建模的可用设施。 因此，这一应用程序将使训练有素且敬业的初级调查员能够开发出独立的 在研究细胞和分子机制方面的职业生涯，这些机制可以转化为解决 公认的肺纤维化-该领域研究的圣杯和巨大的未得到满足的临床需求。

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.