Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis
Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis
批准号:
10352439
负责人:
MARC L PETERS-GOLDEN
金额:
$92.84万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-03-25 至 2026-02-28
关键词:
AllergensAlveolar MacrophagesApoptosisAwardBiologyBortezomibCISH geneCellsCellular biologyCyclic AMPDinoprostoneDiseaseEpithelial CellsFOXM1 geneFibroblastsFoundationsFundingGenetic TranscriptionHealthHomeostasisInflammatoryLeadershipLiposomesLungLung diseasesMalignant - descriptorMediatingMentorsMolecularMolecular BiologyPathogenicityPharmaceutical PreparationsPhysiciansPopulationPrincipal InvestigatorProcessPropertyProteomeProto-OncogenesPulmonary FibrosisPulmonary InflammationQualifyingRegulationReportingResearchResearch SupportResistanceRoleScientistSeminalServicesSignal TransductionStimulusUnited States National Institutes of Healthbronchial epitheliumcancer cellcareercell typeclinical practicedesignextracellular vesiclesinnovationinsightmacrophagenovelnovel therapeutic interventionprogramspulmonary functionscience educationtranscription factortumorigenic
中文摘要
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。
英文摘要
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.
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科研奖励(0)
会议论文
Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis
-
批准号:9900069
-
项目类别:
-
资助金额:$92.84万
-
财政年份:2019
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis
-
批准号:10561635
-
项目类别:
-
资助金额:$93.6万
-
财政年份:2019
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Novel Functions of Lung Macrophages and Fibroblasts in Pulmonary Inflammation and Fibrosis
-
批准号:10112297
-
项目类别:
-
资助金额:$92.84万
-
财政年份:2019
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk
-
批准号:9103201
-
项目类别:
-
资助金额:$56.53万
-
财政年份:2015
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk
-
批准号:9257198
-
项目类别:
-
资助金额:$57.78万
-
财政年份:2015
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk
-
批准号:8961063
-
项目类别:
-
资助金额:$50.13万
-
财政年份:2015
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of fibroblast function by prostaglandin E2 and plasminogen activation
-
批准号:7728502
-
项目类别:
-
资助金额:$37.97万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of fibroblast function by prostaglandin E2 and plasminogen activation
-
批准号:8294649
-
项目类别:
-
资助金额:$37.59万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of fibroblast function by prostaglandin E2 and plasminogen activation
-
批准号:7910714
-
项目类别:
-
资助金额:$37.97万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation
-
批准号:8665457
-
项目类别:
-
资助金额:$39.35万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation
-
批准号:8504174
-
项目类别:
-
资助金额:$37.01万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of fibroblast function by prostaglandin E2 and plasminogen activation
-
批准号:8080237
-
项目类别:
-
资助金额:$37.97万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation
-
批准号:9066748
-
项目类别:
-
资助金额:$38.88万
-
财政年份:2009
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Eisosanoid imbalance in fibrotic lung disease
-
批准号:6565045
-
项目类别:
-
资助金额:$20.88万
-
财政年份:2001
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
DEFICIENT CYCLOOXYGENASE EXPRESSION IN IPF FIBROBLASTS
-
批准号:6410566
-
项目类别:
-
资助金额:$20.88万
-
财政年份:2000
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
DEFICIENT CYCLOOXYGENASE EXPRESSION IN IPF FIBROBLASTS
-
批准号:6302443
-
项目类别:
-
资助金额:$25.55万
-
财政年份:1999
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
DEFICIENT CYCLOOXYGENASE EXPRESSION IN IPF FIBROBLASTS
-
批准号:6110713
-
项目类别:
-
资助金额:$25.55万
-
财政年份:1998
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
LEUKOTRIENES AND PULMONARY ANTIBACTERIAL DEFENSE
-
批准号:2735406
-
项目类别:
-
资助金额:$22.0万
-
财政年份:1997
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Eicosanoids and Lung Macrophage Antimicrobial Mechanisms
-
批准号:7244319
-
项目类别:
-
资助金额:$32.2万
-
财政年份:1997
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
Eicosanoids and lung macrophage antimicrobial mechanisms
-
批准号:7649772
-
项目类别:
-
资助金额:$38.3万
-
财政年份:1997
-
负责人:MARC L PETERS-GOLDEN
-
依托单位:
海外基金