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

这个OIA应用程序的PI是一位具有杰出贡献记录的内科科学家 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，以及这些过程被失调的机制 炎症性和纤维性疾病。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(Fibs)-符合条件 R01奖项目前为每一项研究提供资金。当前的AM项目建立在我们以前的基础上 肺泡巨噬细胞分泌细胞因子信号转导抑制因子3(SOCS3)的研究 (EVS)可被上皮细胞(ECs)内化以抑制促炎JAK状态 发信号。授权期内的目标是描述：a)AM SOCS3在电动汽车内的包装是可以调节的；b)AM来源电动汽车的全球蛋白质组； C)AM EVS(和含SOCS3的人工脂质体)对变应原激活的影响 支气管内皮细胞中的炎症信号；d)囊泡型SOCS3对恶性肿瘤的作用 内皮细胞的转化与癌细胞的致瘤特性。在新的方向上，我们将 阐明自我调节的刺激、信号、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 建立在正在进行的研究基础上，以了解信号和转录机制涉及 纤维蛋白原的促纤维化作用。授权期内的目标是：a) 转录因子BEST叉头盒M1(FOXM1)的作用及作用机制 已知的原癌基因，但以前从未在Fibs-in Mediating Fib中进行过研究 向高致病性肌纤维分化及其对细胞凋亡的抵抗；b)相互作用 FOXM1和其他转录因子；以及c)前列腺素E_2循环的机制 AMP信号抑制FOXM1和Fib的激活及其在几种分子中的诱导作用 在这样的抑制下刹车。新的方向包括表征药物的作用机制 Bortezomib抑制Fib激活不依赖于蛋白酶体的抑制和阐明 环化AMP对FIBS和ECs增殖相反作用的机制。这 内审办将支持国际肺组织的肺细胞创新和翻译相关研究方案 和分子生物学，同时允许他增加对指导和 教育和专业服务。

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.