Caveolin-1 regulation of altered functions of scleroderma fibrocytes
Caveolin-1 对硬皮病纤维细胞功能改变的调节
基本信息
- 批准号:7895783
- 负责人:
- 金额:$ 7.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-17 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelApoptosisBehaviorBleomycinBloodBreathingCD34 geneCell physiologyCell surfaceCellsChemotaxisCollagenDiseaseExhibitsFibroblastsFibrosisGelatinase BGoalsHamman-Rich syndromeHumanITGAM geneIn VitroInflammationInflammatoryLengthLungLung diseasesMAPK8 geneMusMyofibroblastPTPRC genePatientsPeptidesPhenotypePlayPneumoniaPopulationPredispositionProteinsReagentRegulationResolutionRoleSclerodermaSignaling MoleculeSmooth Muscle Actin Staining MethodStructure of parenchyma of lungSurfaceTertiary Protein StructureTestingTransplantationWorkWound Healingcaveolin 1cell typechemokine receptorcytokineeffective therapyimmune functionin vivolung injurymonocytemouse modeloverexpressionperipheral bloodprogenitorreceptor expressionresearch studyscaffold
项目摘要
DESCRIPTION (provided by applicant):
It was originally assumed that the cells in fibrotic lung tissue that overexpress collagen are resident fibroblasts. Increasing evidence now suggests that cells of hematopoetic origin called fibrocytes migrate into damaged lung tissue where they participate in collagen overexpression and differentiate into fibroblasts. Fibrocytes are derived from monocytes and exhibit both fibroblastic (collagen) and monocyte/hematopoetic surface markers. Previous studies strongly suggest that caveolin-1 is a key signaling molecule in the monocyte-fibrocyte- fibroblast lineage and is responsible for functional differences between these cells isolated from lung fibrosis patients and control subjects. These studies (and our proposed studies) have made good use of the caveolin- 1 scaffolding domain (CSD) peptide which, when synthesized as a fusion peptide with the Antennapedia internalization sequence, enters cells and mimics the function of full-length caveolin-1. Key observations are: Considerably less caveolin-1 is present in monocytes, fibrocytes, and fibroblasts from scleroderma lung disease patients than in the same cell types from control subjects; This decrease in caveolin-1 expression in cells from scleroderma patients increases the activation of signaling molecules and the expression of several proteins involved in lung fibrosis including collagen, 1-smooth muscle actin, and MMP-9; Decreased caveolin-1 expression in scleroderma monocytes promotes their differentiation into fibrocytes; and CSD peptide treatment in vivo promotes the resolution of both pulmonary inflammation and fibrosis in mice receiving intratracheal bleomycin. These observations strongly support the hypothesis that the low levels of caveolin-1 in their monocytes, fibrocytes, and fibroblasts play a critical role in the susceptibility of IPF and scleroderma patients to lung fibrosis. To test this hypothesis, we will: 1) Characterize the functional differences between normal and scleroderma monocytes and fibrocytes and the regulation of these functions by caveolin-1, ERK, and JNK; and 2) Determine whether the beneficial effect of CSD peptide treatment on bleomycin-induced lung injury/fibrosis in vivo involves effects of the CSD peptide on fibrocyte behavior. These experiments will be performed using mice transplanted with EGFP+ monocytes and EGFP+ fibrocytes. The results of these experiments will bring us closer to our goal of using the CSD peptide or a related reagent as a treatment for lung fibrosis in human patients by elucidating the mechanism(s) through which the CSD peptide inhibits the progression of lung fibrosis in an animal model (bleomycin-treated mice).
描述(由申请人提供):
最初假设纤维化肺组织中过度表达胶原的细胞是常驻成纤维细胞。现在越来越多的证据表明,造血来源的细胞称为纤维细胞迁移到受损的肺组织中,在那里它们参与胶原蛋白过度表达并分化成纤维细胞。纤维细胞来源于单核细胞,并表现出成纤维细胞(胶原)和单核细胞/造血表面标志物。先前的研究强烈表明,小窝蛋白-1是单核细胞-纤维细胞-成纤维细胞谱系中的关键信号分子,并且负责从肺纤维化患者和对照受试者分离的这些细胞之间的功能差异。这些研究(和我们提出的研究)已经很好地利用了小窝蛋白-1支架结构域(CSD)肽,当合成为融合肽时,与内吞肽序列,进入细胞并模拟全长小窝蛋白-1的功能。主要意见如下:与来自对照受试者的相同细胞类型相比,来自硬皮病肺病患者的单核细胞、纤维细胞和成纤维细胞中存在相当少的小窝蛋白-1;来自硬皮病患者的细胞中小窝蛋白-1表达的这种降低增加了信号传导分子的活化和参与肺纤维化的几种蛋白质的表达,所述蛋白质包括胶原蛋白、1-平滑肌肌动蛋白和MMP-9;硬皮病单核细胞中小窝蛋白-1表达的降低促进其分化为纤维细胞;并且CSD肽在体内处理促进了接受气管内博莱霉素的小鼠中肺部炎症和纤维化的消退。这些观察结果强烈支持了这样的假设,即单核细胞、纤维细胞和成纤维细胞中的低水平小窝蛋白-1在IPF和硬皮病患者对肺纤维化的易感性中起关键作用。为了检验这一假设,我们将:1)表征正常和硬皮病单核细胞和纤维细胞之间的功能差异以及小窝蛋白-1、ERK和JNK对这些功能的调节;和2)确定CSD肽治疗对体内博来霉素诱导的肺损伤/纤维化的有益作用是否涉及CSD肽对纤维细胞行为的作用。这些实验将使用移植有EGFP+单核细胞和EGFP+纤维细胞的小鼠进行。这些实验的结果将使我们更接近于我们的目标,即通过阐明CSD肽在动物模型(博来霉素处理的小鼠)中抑制肺纤维化进展的机制,使用CSD肽或相关试剂作为人类患者中肺纤维化的治疗。
项目成果
期刊论文数量(0)
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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ELENA TOURKINA其他文献
ELENA TOURKINA的其他文献
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{{ truncateString('ELENA TOURKINA', 18)}}的其他基金
Caveolin-1 Regulates Monocyte-Fibrocyte Lineage Cell Functions via CXCR4
Caveolin-1 通过 CXCR4 调节单核细胞-纤维细胞谱系细胞功能
- 批准号:
8711286 - 财政年份:2012
- 资助金额:
$ 7.38万 - 项目类别:
Caveolin-1 Regulates Monocyte-Fibrocyte Lineage Cell Functions via CXCR4
Caveolin-1 通过 CXCR4 调节单核细胞-纤维细胞谱系细胞功能
- 批准号:
8511571 - 财政年份:2012
- 资助金额:
$ 7.38万 - 项目类别:
Caveolin-1 Regulates Monocyte-Fibrocyte Lineage Cell Functions via CXCR4
Caveolin-1 通过 CXCR4 调节单核细胞-纤维细胞谱系细胞功能
- 批准号:
8369455 - 财政年份:2012
- 资助金额:
$ 7.38万 - 项目类别:
Caveolin-1 regulation of altered functions of scleroderma fibrocytes
Caveolin-1 对硬皮病纤维细胞功能改变的调节
- 批准号:
8136776 - 财政年份:2011
- 资助金额:
$ 7.38万 - 项目类别:
Caveolin-1 regulation of altered functions of scleroderma fibrocytes
Caveolin-1 对硬皮病纤维细胞功能改变的调节
- 批准号:
7574277 - 财政年份:2009
- 资助金额:
$ 7.38万 - 项目类别:
Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease
Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用
- 批准号:
7643961 - 财政年份:2007
- 资助金额:
$ 7.38万 - 项目类别:
Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease
Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用
- 批准号:
7440223 - 财政年份:2007
- 资助金额:
$ 7.38万 - 项目类别:
Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease
Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用
- 批准号:
7878837 - 财政年份:2007
- 资助金额:
$ 7.38万 - 项目类别:
Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease
Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用
- 批准号:
7263532 - 财政年份:2007
- 资助金额:
$ 7.38万 - 项目类别:
Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease
Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用
- 批准号:
8099597 - 财政年份:2007
- 资助金额:
$ 7.38万 - 项目类别:
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