Fibroblast Biology and Pulmonary Fibrosis
成纤维细胞生物学和肺纤维化
基本信息
- 批准号:10661596
- 负责人:
- 金额:$ 48.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAreaBiologyCalciumCellsChloride ChannelsChloridesDataDeteriorationDiseaseDisease modelFOXO3A geneFibroblastsFibrosisGenesHumanImmunohistochemistryInjuryLungLysineMAPK7 geneMediatingMesenchymalModelingMyofibroblastNeuronsPathogenesisPathologicPathway interactionsPatientsPhosphorylationPhosphotransferasesProcessProliferatingProtein KinaseProteinsPulmonary FibrosisRoleSignal TransductionSmall Interfering RNATestingTransforming Growth Factor betaWestern Blottingalveolar epitheliumchloride-cotransporter potassiumconditional knockoutconstitutive expressioncytokineeffective therapyfibroblast-activating factorfibrotic lungidiopathic pulmonary fibrosisin vivoknock-downmigrationmouse modelnoveloverexpressionpharmacologicpulmonary functionresponsesingle-cell RNA sequencingsymportertranscriptomewound healing
项目摘要
PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring of the lungs resulting in
deterioration in lung function with a median survival of 3.5 years. Pulmonary fibrosis is thought to be a disorder
of abnormal wound healing, wherein the initial trigger to the fibrotic response is injury to the alveolar
epithelium, followed by an exuberant, non-resolving wound-healing response. TGF-β is the key cytokine in the
pathogenesis of pulmonary fibrosis. TGF-β-driven differentiation of fibroblasts into myofibroblasts is a key
process in the pathogenesis of pulmonary fibrosis; however, the mechanisms of myofibroblast activation are
not completely understood.
In an unbiased approach using microarray studies, we identified Anoctamin-1 (ANO1), also known as
TMEM16A, as one of highly upregulated genes in response to TGF-β contributing to the proliferation, migration
and differentiation of lung fibroblasts to myofibroblasts. Our data also suggest that ANO1 is increased in the
lungs of IPF patients and is localized to the fibrotic areas in the IPF lung. The role of ANO1 in myofibroblast
activation and pulmonary fibrosis has been poorly investigated. Since ANO1 is a calcium-activated chloride
channel, we evaluated the role of chloride-sensitive protein kinase, With-No-Lysine Kinase-1 (WNK1), which
similarly to ANO1 contributed to myofibroblast activation. Based on our preliminary data, we hypothesize that
ANO1 is a pro-fibrotic protein promoting myofibroblast activation and pulmonary fibrosis through WNK1
pathway. To test our hypothesis, we propose the following specific aims:
Specific Aim #1. Determine how ANO1-mediated control of intracellular chloride levels activates human lung
fibroblasts (HLFs).
Specific Aim #2. Determine the signaling mechanisms of fibroblast activation through ANO1 and WNK1 in HLF.
Specific Aim #3. Elucidate the profibrotic role of ANO1 in the lung in vivo by a conditional knockout of ANO1 in
fibroblasts.
项目摘要
特发性肺纤维化(IPF)是一种以肺部进行性瘢痕形成为特征的疾病,
肺功能恶化,中位生存期为3.5年。肺纤维化被认为是一种
其中纤维化反应的初始触发因素是肺泡损伤,
上皮,随后是旺盛的、非消退的伤口愈合反应。转化生长因子-β是肿瘤细胞中的关键细胞因子,
肺纤维化的发病机制。TGF-β驱动的成纤维细胞向肌成纤维细胞的分化是一个关键
在肺纤维化的发病过程中;然而,肌成纤维细胞活化的机制是
不完全理解。
在使用微阵列研究的无偏方法中,我们鉴定了Anoctamin-1(ANO 1),也称为
TMEM 16 A作为TGF-β诱导的高表达基因之一,参与细胞的增殖、迁移和凋亡,
以及肺成纤维细胞向肌成纤维细胞的分化。我们的数据还表明,ANO 1在
在IPF患者的肺中存在纤维化,并且局限于IPF肺中的纤维化区域。ANO 1在肌成纤维细胞中的作用
活化和肺纤维化的研究很少。由于ANO 1是钙激活的氯化物,
通道,我们评估了氯敏感蛋白激酶,无赖氨酸激酶-1(WNK 1)的作用,
与ANO 1类似,ANO 1促进肌成纤维细胞活化。根据我们的初步数据,我们假设,
ANO 1是通过WNK 1促进肌成纤维细胞活化和肺纤维化的促纤维化蛋白
通路为了检验我们的假设,我们提出了以下具体目标:
具体目标#1。确定ANO 1介导的细胞内氯离子水平控制如何激活人肺
成纤维细胞(HLF)。
具体目标#2确定HLF中通过ANO 1和WNK 1激活成纤维细胞的信号机制。
具体目标#3通过条件性敲除ANO 1,阐明ANO 1在体内肺中的促纤维化作用,
成纤维细胞
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling.
- DOI:10.3389/fphys.2020.590262
- 发表时间:2020
- 期刊:
- 影响因子:4
- 作者:Dulin NO
- 通讯作者:Dulin NO
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NICKOLAI O DULIN其他文献
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{{ truncateString('NICKOLAI O DULIN', 18)}}的其他基金
Control of myofibroblast activation and pulmonary fibrosis by Na/K-ATPase
Na/K-ATP酶控制肌成纤维细胞活化和肺纤维化
- 批准号:
9130388 - 财政年份:2015
- 资助金额:
$ 48.22万 - 项目类别:
Activation of protein kinase A by endothelin-1
内皮素 1 激活蛋白激酶 A
- 批准号:
7214750 - 财政年份:2005
- 资助金额:
$ 48.22万 - 项目类别:
Activation of protein kinase A by endothelin-1
内皮素 1 激活蛋白激酶 A
- 批准号:
7418987 - 财政年份:2005
- 资助金额:
$ 48.22万 - 项目类别:
Activation of protein kinase A by endothelin-1
内皮素 1 激活蛋白激酶 A
- 批准号:
6871724 - 财政年份:2005
- 资助金额:
$ 48.22万 - 项目类别:
Activation of protein kinase A by endothelin-1
内皮素 1 激活蛋白激酶 A
- 批准号:
7623843 - 财政年份:2005
- 资助金额:
$ 48.22万 - 项目类别:
Activation of protein kinase A by endothelin-1
内皮素 1 激活蛋白激酶 A
- 批准号:
7054651 - 财政年份:2005
- 资助金额:
$ 48.22万 - 项目类别:
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