Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis

肺巨噬细胞和成纤维细胞在肺部炎症和纤维化中的新功能

• 批准号: 10112297
• 负责人: MARC L PETERS-GOLDEN
• 金额: $ 92.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112297
• 关键词: Allergens; Alveolar Macrophages; Apoptosis; Award; Biology; Bortezomib; CISH gene; Cells; Cellular biology; Cyclic AMP; Dinoprostone; Disease; Epithelial Cells; FOXM1 gene; Fibroblasts; Foundations; Funding; Genetic Transcription; Health; Homeostasis; Inflammatory; Leadership; Liposomes; Lung; Lung diseases; Malignant - descriptor; Mediating; Mentors; Molecular; Molecular Biology; Pathogenicity; Pharmaceutical Preparations; Physicians; Population; Principal Investigator; Process; Property; Proteome; Proto-Oncogenes; Pulmonary Fibrosis; Pulmonary Inflammation; Qualifying; Regulation; Reporting; Research; Research Support; Resistance; Role; Scientist; Seminal; Services; Signal Transduction; Stimulus; United States National Institutes of Health; bronchial epithelium; cancer cell; career; cell type; clinical practice; design; extracellular vesicles; innovation; insight; macrophage; novel; novel therapeutic intervention; programs; pulmonary function; science education; transcription factor; tumorigenic

The PI of this OIA application is a physician-scientist with an outstanding record of contributions to science, education and mentoring, clinical practice, and professional leadership and service. During his 30-year career of NIH-supported research, he has made seminal discoveries that have advanced our understanding of the normal biology and regulatory processes governing key lung cells, and the mechanisms by which these processes are dysregulated during inflammatory and fibrotic diseases. His research program is predominantly focused on two important cell types – alveolar macrophages (AMs) and lung fibroblasts (Fibs) – with qualifying R01 awards currently funding studies of each. The current AM project builds upon our prior report that AMs secrete suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs) that can be internalized by epithelial cells (ECs) to dampen pro-inflammatory JAK-STAT signaling. Objectives during the award period are to characterize: a) mechanisms by which AM packaging of SOCS3 within EVs can be modulated; b) the global proteome of AM-derived EVs; c) effects of AM EVs (and artificial SOCS3-containing liposomes) on allergen-activated inflammatory signaling in bronchial ECs; and d) effects of vesicular SOCS3 on malignant transformation of ECs and tumorigenic properties of cancer cells. In a new direction, we will elucidate the stimuli, signaling, transcriptional, and regulatory mechanisms governing self- replication of AMs in comparison with other macrophage populations. The current Fib project builds upon ongoing studies to understand signaling and transcriptional mechanisms involved in pro-fibrotic properties of Fibs. Objectives during the award period are to characterize: a) the actions and responsible mechanisms of forkhead box M1 (FOXM1) – a transcription factor best known as a proto-oncogene but never previously studied in Fibs – in mediating Fib differentiation to highly pathogenic myoFibs and their apoptosis resistance; b) the interplay of FOXM1 with other transcription factors; and c) the mechanisms by which prostaglandin E2-cyclic AMP signaling inhibits FOXM1 and Fib activation, and the role of induction of several molecular brakes in such inhibition. New directions include characterizing mechanisms by which the drug bortezomib inhibits Fib activation independent of proteasomal inhibition and elucidating mechanisms to explain opposing actions of cyclic AMP on proliferation of Fibs vs. ECs. This OIA will support the PI's program of innovative and translationally relevant research in lung cell and molecular biology while allowing him to increase his commitment to mentoring and educational and professional service.

本OIA应用程序的PI是一位具有杰出贡献记录的医生科学家 科学、教育和指导、临床实践以及专业领导和服务。 在他30年的NIH支持的研究生涯中，他取得了开创性的发现， 促进了我们对正常生物学和调控过程的理解， 关键的肺细胞，以及这些过程中失调的机制， 炎症和纤维化疾病。他的研究计划主要集中在两个方面 重要的细胞类型-肺泡巨噬细胞（AM）和肺成纤维细胞（Fib）-具有资格 R 01奖目前资助每一项研究。目前的AM项目建立在我们以前的基础上 报道AM在细胞外囊泡内分泌细胞因子信号传导抑制因子3（SOCS 3 (EVs)它可以被上皮细胞（EC）内化，以抑制促炎性JAK-STAT 发信号。奖励期间的目标是表征：a）AM 可以调节SOCS 3在EV内的包装; B）AM衍生EV的全局蛋白质组; c）AMEV（和含有人工SOCS 3的脂质体）对过敏原活化的细胞的作用 d）囊泡SOCS 3对支气管EC中的恶性炎症信号传导的影响 EC的转化和癌细胞的致瘤性。在一个新的方向，我们将 阐明刺激，信号，转录和调节机制，管理自我- 与其他巨噬细胞群体相比，AM的复制。目前的Fib项目 建立在正在进行的研究，以了解信号和转录机制参与 Fibs的促纤维化特性。授予期间的目标是：a） 叉头框M1（FOXM 1）-转录因子的作用和负责机制 被称为原癌基因，但以前从未在纤维蛋白原中研究过-在介导纤维蛋白原中， 分化为高致病性肌纤维和它们的凋亡抗性; B） FOXM 1与其他转录因子;和c）前列腺素E2-环 AMP信号转导抑制FOXM 1和Fib的活化，并诱导几种分子的作用， 在这种抑制中刹车。新的研究方向包括描述药物的作用机制， 硼替佐米不依赖于蛋白酶体抑制而抑制Fib活化， 机制来解释环AMP对FIB与EC增殖的相反作用。这 OIA将支持PI的肺细胞创新和预防相关研究计划 和分子生物学，同时使他能够增加他对指导的承诺， 教育和专业服务。