Mechanism of Fibroblast Growth Factor 2-Mediated Alveolar Epithelial Repair

成纤维细胞生长因子2介导的肺泡上皮修复机制

• 批准号: 10170402
• 负责人: Robert David Guzy
• 金额: $ 16.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170402
• 关键词: Acute Lung Injury; Address; Adult; Adult Respiratory Distress Syndrome; Advisory Committees; Affect; Affinity; Alveolar Macrophages; Basic Science; Biology; Biopsy; Bleomycin; Bone Marrow; Cells; Cessation of life; Chicago; Chimera organism; Clinical Trials; Critical Care; Data; Development; Development Plans; Discipline; Doctor of Philosophy; Epithelial; Epithelial Cells; FGF2 gene; FGF7 gene; Feedback; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Foundations; Functional disorder; Funding; Future; Genetic Transcription; Goals; Growth Factor; Heart; Hindlimb; Human; Immune; Impairment; Infection; Influenza A virus; Injury; Internal Medicine; International; Intervention; Investigation; Knock-out; Knowledge; Length of Stay; Ligands; Lung; Lung diseases; Manuscripts; Mediating; Medicine; Mentors; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Population; Preparation; Process; Proliferating; Publications; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Pulmonology; Recombinants; Recovery; Research; Research Personnel; Research Training; Role; Scientist; Signal Transduction; Skin; Source; Stromal Cells; Supervision; Supportive care; Testing; Therapeutic Agents; TimeLine; Tissues; Training; Translating; United States National Institutes of Health; Universities; Vocational Guidance; Work; alveolar epithelium; base; care outcomes; career; career development; cell injury; epithelial injury; epithelial repair; experience; fibroblast growth factor receptor 4; human disease; improved; in vivo; indium-bleomycin; injury recovery; interest; lung injury; mRNA Expression; macrophage; monocyte; mortality; mouse model; next generation; novel therapeutics; overexpression; progenitor; receptor binding; response; response to injury; skills; therapeutic evaluation; tissue repair; transcriptome sequencing; transcriptomics; translational study

PROJECT SUMMARY This proposal describes a five-year research and training plan that will facilitate the transition of Dr. Robert Guzy, MD, PhD to an independent academic researcher. Dr. Guzy is a cell and molecular biologist and adult pulmonologist at the University of Chicago, and is building a career as a physician scientist with an interest in lung injury and pulmonary fibrosis. He has a strong background in basic science research and medicine and has completed post-graduate training in Internal Medicine and Pulmonary/Critical Care Medicine. The primary training goal of this K08 proposal is to provide the framework and support necessary for Dr. Guzy to 1) extend his experience with murine models of lung injury, 2) build a fund of knowledge in macrophage biology, 3) develop expertise in translational studies, 4) develop expertise in transcriptomics, and 5) transition to independent scientific investigation in pulmonary disease. This work will be carried out at The University of Chicago under the supervision of Dr. Gokhan Mutlu, MD. The University of Chicago is renowned for its strength in many research disciplines, including translational pulmonary medicine. Dr. Mutlu is an international leader in lung injury research and macrophage biology, and has a highly successful track record of mentoring. An advisory committee with diverse expertise will provide career guidance and scientific feedback. A detailed career development plan is proposed that includes a timeline for development of new skills, preparation of manuscripts for publication, and an eventual R01 application in a pathway to independence. The proposed research plan will focus on mechanistic studies of FGF2 signaling in lung injury. Preliminary studies performed by Dr. Guzy demonstrate that FGF2 is expressed in macrophages in response to lung injury in mice and humans. Furthermore, mice lacking FGF2 (Fgf2-/-) have increased mortality and deficient alveolar epithelial recovery in response to bleomycin. This study proposes a model in which macrophage-derived FGF2 is required for recovery from lung injury by directly promoting proliferation of lung epithelium and subsequent differentiation into mature alveolar epithelial cells. This will be approached with three Specific Aims: Aim 1: Determine the requirement of macrophage-derived FGF2 expression in response to lung injury. Aim 2: Determine the requirement of FGFRs in Type 2 AECs for recovery after lung injury. Aim 3: Determine the capacity for FGF2 to provide an enhanced reparative signal after lung injury. In total, these studies will be critical for developing a mechanism of FGF2/FGFR-mediated epithelial recovery after lung injury, and will be the basis for future applications of FGF2 to promote recovery in patients with ARDS. Additionally, results of this project will serve as a foundation for future NIH R01 applications and a career as an independent pulmonary physician scientist.

项目概要 该提案描述了一项为期五年的研究和培训计划，该计划将促进罗伯特博士的过渡 Guzy，医学博士、博士，独立学术研究员。 Guzy 博士是一位细胞和分子生物学家，也是一名成人 芝加哥大学的肺科医生，正在建立一名医师科学家的职业生涯，对以下领域感兴趣 肺损伤和肺纤维化。他拥有深厚的基础科学研究和医学背景 已完成内科和肺/重症监护医学的研究生培训。初级 K08 提案的培训目标是为 Guzy 博士提供必要的框架和支持，以 1) 扩展 他在小鼠肺损伤模型方面的经验，2) 建立了巨噬细胞生物学知识库，3) 发展转化研究方面的专业知识，4) 发展转录组学方面的专业知识，以及 5) 过渡到 肺部疾病的独立科学研究。 这项工作将在医学博士 Gokhan Mutlu 博士的监督下在芝加哥大学进行。 芝加哥大学以其在许多研究学科的实力而闻名，包括转化 肺科医学。 Mutlu 博士是肺损伤研究和巨噬细胞生物学领域的国际领导者， 拥有非常成功的指导记录。具有多元化专业知识的咨询委员会将提供 职业指导和科学反馈。提出详细的职业发展计划，其中包括 开发新技能、准备出版手稿以及最终 R01 的时间表 应用在通往独立的道路上。 拟议的研究计划将重点关注肺损伤中 FGF2 信号传导的机制研究。初步的 Guzy 博士进行的研究表明，FGF2 在巨噬细胞中表达以响应肺损伤 在小鼠和人类中。此外，缺乏 FGF2 (Fgf2-/-) 的小鼠死亡率增加且肺泡缺陷 博莱霉素对上皮细胞的恢复。这项研究提出了一个模型，其中巨噬细胞衍生 FGF2 是肺损伤恢复所必需的，可直接促进肺上皮细胞增殖 并随后分化为成熟的肺泡上皮细胞。这将通过三个方面来实现 具体目标： 目标 1：确定巨噬细胞衍生的 FGF2 表达对肺反应的要求 受伤。目标 2：确定 2 型 AEC 中肺损伤后恢复对 FGFR 的需求。目标 3： 确定 FGF2 在肺损伤后提供增强的修复信号的能力。 总的来说，这些研究对于开发 FGF2/FGFR 介导的上皮细胞的机制至关重要。 肺损伤后的恢复，将成为未来应用FGF2促进患者康复的基础 患有急性呼吸窘迫综合征。此外，该项目的结果将作为未来 NIH R01 应用的基础和 作为一名独立的肺科医师科学家。

项目成果

Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation.

• DOI: 10.1002/path.5106
• 发表时间: 2018-09
• 期刊: The Journal of pathology
• 作者: Koo HY;El-Baz LM;House S;Cilvik SN;Dorry SJ;Shoukry NM;Salem ML;Hafez HS;Dulin NO;Ornitz DM;Guzy RD
• 通讯作者: Guzy RD

Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis.

• DOI: 10.1136/bmjresp-2022-001391
• 发表时间: 2023-02
• 期刊: BMJ OPEN RESPIRATORY RESEARCH
• 影响因子: 4.1
• 作者: Huang, Yong;Guzy, Rob;Ma, Shwu-Fan;Bonham, Catherine A.;Jou, Jonathan;Schulte, Jefree J.;Kim, John S.;Barros, Andrew J.;Espindola, Milena S.;Husain, Aliya N.;Hogaboam, Cory M.;Sperling, Anne, I;Noth, Imre
• 通讯作者: Noth, Imre

Fibroblast Growth Factor 2 Augments Transforming Growth Factor Beta 1 Induced Epithelial-mesenchymal Transition in Lung Cell Culture Model.

• DOI: 10.18502/ijaai.v19i4.4110
• 发表时间: 2020-08-25
• 期刊: Iranian journal of allergy, asthma, and immunology
• 作者: El-Baz LMF;Shoukry NM;Hafez HS;Guzy RD;Salem ML
• 通讯作者: Salem ML