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

基本信息

批准号：
9900069
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
项目类别：
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/9900069
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 Respiratory physiology 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 science education transcription factor tumorigenic

项目摘要

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.

此 OIA 应用程序的 PI 是一位具有杰出贡献记录的医师科学家科学、教育和指导、临床实践以及专业领导和服务。在 NIH 支持的 30 年研究生涯中，他取得了开创性的发现：增进了我们对正常生物学和调控过程的理解关键的肺细胞，以及这些过程在过程中失调的机制他的研究项目主要集中在两种疾病上。重要的细胞类型 – 肺泡巨噬细胞 (AM) 和肺成纤维细胞 (Fib) – 符合资格 R01 目前正在资助每个项目的研究。当前的 AM 项目建立在我们之前的基础上。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 (SOCS3) (EV) 可以被上皮细胞 (EC) 内化以抑制促炎性 JAK-STAT 奖励期间的目标是描述： a) AM 所采用的机制。可以调节 EV 中 SOCS3 的包装；b) AM 衍生的 EV 的全局蛋白质组； c) AM EV（和含有 SOCS3 的人工脂质体）对过敏原激活的影响支气管 EC 中的炎症信号；d) 囊泡 SOCS3 对恶性细胞的影响 ECs 的转化和癌细胞的致瘤特性，我们将在一个新的方向上进行。阐明控制自我的刺激、信号传导、转录和调节机制 AM 的复制与其他巨噬细胞群体的比较当前的 Fib 项目。以正在进行的研究为基础，以了解参与的信号传导和转录机制 Fib 的促纤维化特性。奖励期间的目标是表征：a) 叉头框 M1 (FOXM1) 的作用和负责机制 – 最好的转录因子被称为原癌基因，但之前从未在 Fib 中进行过研究——在调节 Fib 中分化为高致病性肌纤维及其细胞凋亡抵抗 b) 的相互作用； FOXM1 与其他转录因子；以及 c) 前列腺素 E2 环化的机制 AMP 信号传导抑制 FOXM1 和 Fib 激活，以及几个分子的诱导作用新的方向包括表征药物的机制。硼替佐米抑制 Fib 激活独立于蛋白酶体抑制并阐明解释环 AMP 对 Fib 与 EC 增殖的相反作用的机制。 OIA 将支持 PI 的肺细胞创新和转化相关研究计划和分子生物学，同时使他能够加大对指导和教育和专业服务。