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：该建议描述了一项为期五年的研究和职业发展计划，旨在支持申请人的发展为独立的物理科学家调查肺肌纤维细胞（MF）的机制分化/清除和肺纤维化分辨率。研究计划：特发性肺纤维化（IPF）是最致命的纤维化肺部疾病，影响了数百万在全球范围内的个人，有限的治疗选择未能逆转纤维化。 MF是 IPF的最终效应细胞，其持久性伤口修复后的持久性 - 凋亡的结果抗性 - 导致进行性肺部疤痕和僵硬，扭曲组织结构和损害气体交换。肺MF的清除 - 通过表型去差异和凋亡的恢复灵敏度 - 有可能解决纤维化。申请人发现肺MF脱不同可以通过不同的过渡表型进行，并且mRNA的转录后调节对这个过程。在此提案中，他将研究内源性抗纤维化制动循环腺苷的作用单磷酸盐（CAMP）及其对主要后调节剂人体抗原R（HUR）的调节在MF脱不同和纤维化分辨率中。申请人和培训计划：申请人拥有MD学位，并完成了内部临床培训医学，肺部和重症监护医学。在他的奖学金和事先研究期间，他有在体外系统和成纤维细胞生物学的基本实验室技术方面获得了经验。作为他职业生涯的一部分开发，适用的将参加旨在发展新知识的修订研究和熟练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体内建模和肺纤维化研究。获取这些新技能和经验将极大地支持他的发展，以研究可以将MF脱离分化和清除的机制，从而促进策略促进纤维化解决。这些领域的培训将在他的经验精神团队的指导下获得通过参加SEMIAR，实验室会议，课程，讲习班和国家会议。他也会接受赠款写作和负责任的研究培训。杰出的机构研究环境为申请人提供了与RNA调查人员互动的丰富机会，分子生物学，肺部和肺外纤维化以及基本和翻译的科学家。将利用用于高级成像，RNA测序和转基因动物建模的可用设施。因此，该应用程序将使训练有素且致力于的初级调查员能够开发独立研究细胞和分子机制的职业，可以将其转化为分辨率建立的肺纤维化 - 该领域的研究的圣杯和巨大的未满足临床需求。