Mechanism of Fibroblast Growth Factor 2-Mediated Alveolar Epithelial Repair

项目总结 该提案描述了一项五年研究和培训计划，该计划将促进罗伯特博士的过渡 Guzy，医学博士，独立学术研究人员。古齐博士是一名细胞和分子生物学家，也是一名成年人 他是芝加哥大学的肺病学家，目前正在从事内科科学家的职业生涯，他对 肺损伤和肺纤维化。他在基础科学研究和医学方面有很强的背景 已完成内科和肺部/重症监护医学的研究生培训。初级阶段 本K08提案的培训目标是为Guzy博士提供必要的框架和支持，以便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方面的知识基金，3) 培养翻译研究方面的专长，4)培养转录学方面的专长，以及5)过渡到 对肺部疾病进行独立的科学研究。 这项工作将在芝加哥大学医学博士Gokhan Mutlu的监督下进行。 芝加哥大学以其在许多研究领域的实力而闻名，包括翻译学 肺内科。穆特鲁博士是肺损伤研究和巨噬细胞生物学的国际领先者， 在指导方面有着非常成功的记录。一个拥有不同专业知识的咨询委员会将提供 职业指导和科学反馈。提出了详细的职业发展计划，其中包括 开发新技能、准备出版手稿的时间表，以及最终的R01 在通往独立的道路上的应用。 拟议的研究计划将侧重于肺损伤中FGF2信号的机制研究。初步 Guzy博士的研究表明，肺损伤后巨噬细胞表达FGF2 在老鼠和人类身上。此外，缺乏FGF2(FGF2-/-)的小鼠死亡率增加，肺泡功能不足 对博莱霉素有反应的上皮恢复。本研究提出了一种巨噬细胞来源的模型 FGF2直接促进肺上皮细胞增殖是肺损伤恢复所必需的 随后分化为成熟的肺泡上皮细胞。这将通过三个步骤来实现 具体目标：目标1：确定肺对巨噬细胞源性FGF2表达的需求 受伤。目的2：确定肺损伤后2型AECs对FGFRs的需求。目标3： 确定FGF2在肺损伤后提供增强修复信号的能力。 总之，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，并将成为未来应用FGF2促进患者恢复的基础 和ARDS一起。此外，该项目的成果将作为未来NIH R01应用的基础和 作为一名独立的肺部内科科学家的职业。

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.