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

肺肌成纤维细胞去分化和纤维化消退取决于 cAMP 介导的 HuR 抑制。

基本信息

批准号：
10661944
负责人：
Sean Michael Fortier
金额：
$ 16.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661944
关键词：
Adenylate Cyclase Affect Animal Model Antigens Apoptosis Apoptotic Architecture Area Award Bioinformatics Biology Bleomycin CRISPR/Cas technology Cell Differentiation process Cell Line Chemosensitization Cicatrix Clinical Clinical Data Collagen Critical Care Cyclic AMP Data Development Development Plans Educational workshop Effector Cell Environment Exhibits Fellowship Fibroblasts Fibrosis Fluorescence Microscopy Forskolin Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gases Gene Expression Gene Expression Profile Generations Genes Grant Human Image Immunofluorescence Microscopy Impairment In Vitro Individual Institution Internal Medicine Investigation Knock-out Knockout Mice Knowledge Ligation Lung Lung diseases Mediating Medicine Mentors Messenger RNA Modeling Molecular Molecular Biology Mus Myofibroblast Patients Phenotype Phosphodiesterase Inhibitors Phosphorylation Physicians Post-Transcriptional Regulation Process Proliferating Proteins Pulmonary Fibrosis RNA RNA-Binding Proteins Reagent Regulation Research Research Design Research Personnel Resistance Resolution Role Scientist Second Messenger Systems Signal Pathway Signal Transduction System Techniques Testing Therapeutic Therapeutic Effect Time Tissues Training Transcript Transgenic Animals Transgenic Mice Translating Translations Untranslated RNA Wild Type Mouse Writing career career development cell dedifferentiation clinical training experience fibrotic lung fibrotic lung disease idiopathic pulmonary fibrosis in vivo in vivo Model inhibitor lung injury mRNA Stability meetings mouse model multidisciplinary novel pharmacologic posttranscriptional research and development responsible research conduct restoration skills trafficking transcriptome sequencing transcriptomics translational impact translational scientist wound healing

项目摘要

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.

项目摘要/摘要：该提案描述了旨在支持申请人的五年研究和职业发展计划晋升为独立医师科学家，研究肺肌成纤维细胞（MF）去-的机制分化/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，影响数百万人世界各地的患者，治疗选择有限，无法逆转已形成的纤维化。 IPF 的最终效应细胞在伤口修复后持续存在——这是其凋亡的结果阻力——导致进行性肺部疤痕和僵硬，扭曲组织结构并损害气体肺 MF 的清除——通过其表型去分化和细胞凋亡的恢复。敏感性——具有解决纤维化的潜力，申请人发现肺 MF 去分化。可以通过不同的过渡表型进行，并且 mRNA 的转录后调控对于在这个过程中，他将研究内源性抗纤维化刹车环腺苷的作用。单磷酸盐 (cAMP) 及其对主要转录后调节因子人类抗原 R (HuR) 的调节 MF 去分化和纤维化消退。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在他的进修期间和之前的研究工作中，他曾从事医学、肺病和重症监护医学方面的研究。作为他职业生涯的一部分，他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。发展，申请人将参与旨在开发新知识和精通 RNA 生物学、CRISPR/Cas9 技术、免疫荧光显微镜、生物信息学和使用新型转基因小鼠进行肺纤维化的体内建模和研究。技能和经验将极大地促进他发展成为一名研究该问题的独立调查员 MF 去分化和清除的机制，从而实现促进纤维化的策略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，并且他还将通过参加研讨会、实验室会议、课程、讲习班和全国会议。接受拨款写作和负责任的研究行为方面的培训。环境为申请人提供了与RNA和RNA研究人员互动的丰富机会分子生物学、肺纤维化和肺外纤维化，以及基础科学家和转化科学家。将利用现有的先进成像、RNA 测序和转基因动物建模设施。因此，该应用程序将使训练有素且忠诚的初级研究员能够开发独立的从事细胞和分子机制研究的职业生涯，这些机制可以转化为解决问题的方法确定的肺纤维化是该领域研究的圣杯，也是巨大的未满足的临床需求。