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: 10561635
• 负责人: MARC L PETERS-GOLDEN
• 金额: $ 93.6万
• 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/10561635
• 关键词: Allergens; Alveolar Macrophages; Apoptosis; Award; Biology; Bortezomib; CISH gene; Cells; Cellular biology; Cyclic AMP; Dinoprostone; Disease; Education; Epithelial Cells; FOXM1 gene; Fibroblasts; Foundations; Funding; Genetic Transcription; Health; Homeostasis; Inflammatory; Leadership; Liposomes; Lung; Lung diseases; Macrophage; Malignant - descriptor; Mediating; Mentors; Molecular; Molecular Biology; Pathogenicity; Pharmaceutical Preparations; Physicians; Population; Principal Investigator; Process; Productivity; Proliferating; Property; Proteome; Proto-Oncogenes; Pulmonary Fibrosis; Pulmonary Inflammation; Qualifying; Regulation; Reporting; Research; Research Support; Resistance; Role; Science; 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; novel; novel therapeutic intervention; programs; pulmonary function; 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.

此OIA申请的PI是一位有杰出贡献记录的医生兼科学家