Type I collagen signaling in lung injury and fibrosis
肺损伤和纤维化中的 I 型胶原信号传导
基本信息
- 批准号:9898421
- 负责人:
- 金额:$ 37.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-05-15 至 2021-09-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelApoptosisApoptoticArchitectureAreaAttenuatedCause of DeathCell DeathCell SurvivalCessation of lifeChronic DiseaseCicatrixClinicalClinical TrialsCollagenCollagen Type ICombined Modality TherapyComplicationCoupledCultured CellsDataDepositionDisease ProgressionEpithelial CellsEquilibriumEventFailureFamilyFeedbackFibrillar CollagenFibroblastsFibrosisHumanImpairmentInhibition of ApoptosisInjuryIntegrin alpha2IntegrinsLeadLinkLungMediatingMediator of activation proteinModalityModelingMusOrganPTK2 genePathologicPathway interactionsPhysiologicalProcessProductionProteinsPulmonary FibrosisReagentReceptor Protein-Tyrosine KinasesRegulationResearchResolutionRespiratory physiologyRoleSignal PathwaySignal TransductionStimulusTestingTherapeuticTherapeutic TrialsTissuesTransforming Growth Factor betaTransgenic MiceTranslatingTyrosinealveolar epitheliumattenuationcrosslinkdiscoidin domain receptor 2discoidin receptorexperimental studyhuman diseaseidiopathic pulmonary fibrosisin vivoinhibitor/antagonistlung injurymimeticsnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsreceptorrecruitrepairedresponseresponse to injurytargeted treatmentwound healing
项目摘要
Title: Type I collagen signaling in lung injury and fibrosis
Abstract/Project Summary
Progressive fibrosis is a complication of many chronic diseases and collectively, organ fibrosis is the
leading cause of death in the US. Although many therapeutic strategies have dramatically attenuated fibrosis in
animal models translating these findings into successful therapies for IPF has proven disappointing with
several negative clinical trials and two new therapies only modestly slowing the progression of disease. Some
have suggested the need for multi-modality therapies targeting different parts of the pro-fibrotic pathway.
The current paradigm is that injury initiates a dynamic repair process that ultimately leads to fibrillar
collagen deposition and scar formation. Progressive fibrosis is characterized by activation of self-amplifying
feed-forward/positive feedback signaling pathways leading to excessive scarring. However, the ubiquity of the
scar formation process after diverse injuries in nearly every tissue suggests that scarring may also be
protective in limiting ongoing cellular and tissue damage and may be necessary to resolve the initial injury.
Attempt at limiting collagen deposition may lead to persistence of the initial inciting stimuli. A more complete
understanding into the linked mechanisms involved in the balance between progressive fibrosis and resolution
of focal injurious stimuli is necessary.
While matrix signaling during fibrosis has been studied, collagen I itself is often regarded as an end
product of fibrosis but we have found that collagen I is also a critical mediator of progressive fibrosis. We have
found that alveolar epithelial cell (AEC) apoptosis is a necessary and sufficient initiator of fibrosis and that a
rigid collagen I matrix blunts the AEC apoptotic response to TGFβ. In vivo, we found that collagen I expression
is induced early after injury and collagen I-deficient mice have sustained lung injury and greater death.
Collagen I signaling also enhances fibroblast recruitment and activation. Collagen can initiate signaling through
specific integrins as well as a family of receptor tyrosine kinsases, the discoidin domain receptors (DDR). Our
preliminary data support important and non-redundant roles for both α2β1 integrin and DDR2 in regulation of
this injury/fibrosis cycle. Thus, type I collagen is likely important in determining whether the response to injury
is limited scar formation versus progressive fibrosis and potentially establishes a dilemma in which failure of
fibrosis in the context of continued TGFβ-induced AEC apoptosis could lead to greater foci of injury and
suboptimal inhibition of profibrotic pathways. Our central hypothesis is type I collagen signaling promotes both
propagation of fibrosis and inhibition of AEC apoptosis but these processes are regulated by distinct pathways.
We will pursue studies aimed at understanding the mechanism of collagen I and its receptors in regulation of
AEC apoptosis and fibroblast activation using reagents currently available in our lab including, primary murine
and human diseased AECs and fibroblasts, decellularized lung matrix from normal human and IPF lungs as
well as lungs from injured transgenic mice, coupled with in vivo experiments using novel transgenic mice.
标题:I型胶原信号在肺损伤和纤维化中的作用
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KEVIN KEEWOUN KIM其他文献
KEVIN KEEWOUN KIM的其他文献
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{{ truncateString('KEVIN KEEWOUN KIM', 18)}}的其他基金
Oxidized Phospholipids Derived from Apoptotic Pneumocytes Drives Macrophage Activation and Initiates Lung Fibrosis
凋亡肺细胞衍生的氧化磷脂驱动巨噬细胞激活并引发肺纤维化
- 批准号:
10470837 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Oxidized Phospholipids Derived from Apoptotic Pneumocytes Drives Macrophage Activation and Initiates Lung Fibrosis
凋亡肺细胞衍生的氧化磷脂驱动巨噬细胞激活并引发肺纤维化
- 批准号:
10293745 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Oxidized Phospholipids Derived from Apoptotic Pneumocytes Drives Macrophage Activation and Initiates Lung Fibrosis
凋亡肺细胞衍生的氧化磷脂驱动巨噬细胞激活并引发肺纤维化
- 批准号:
10616814 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis
靶向成纤维细胞盘状结构域受体 2 用于肺纤维化免疫治疗
- 批准号:
10362183 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis
靶向成纤维细胞盘状结构域受体 2 用于肺纤维化免疫治疗
- 批准号:
10532241 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Function of epithelial-mesenchymal transition during pulmonary fibrosis
上皮间质转化在肺纤维化过程中的作用
- 批准号:
8821656 - 财政年份:2012
- 资助金额:
$ 37.46万 - 项目类别:
Function of epithelial-mesenchymal transition during pulmonary fibrosis
上皮间质转化在肺纤维化过程中的作用
- 批准号:
8646991 - 财政年份:2012
- 资助金额:
$ 37.46万 - 项目类别:
Type I collagen signaling in lung injury and fibrosis
肺损伤和纤维化中的 I 型胶原信号传导
- 批准号:
9308528 - 财政年份:2012
- 资助金额:
$ 37.46万 - 项目类别:
Function of epithelial-mesenchymal transition during pulmonary fibrosis
上皮间质转化在肺纤维化过程中的作用
- 批准号:
8290684 - 财政年份:2012
- 资助金额:
$ 37.46万 - 项目类别:
Function of epithelial-mesenchymal transition during pulmonary fibrosis
上皮间质转化在肺纤维化过程中的作用
- 批准号:
8469897 - 财政年份:2012
- 资助金额:
$ 37.46万 - 项目类别:
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