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
• 负责人: ELENA TOURKINA
• 金额: $ 7.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7574277
• 关键词: Animal Model; Apoptosis; Behavior; Bleomycin; Blood; Breathing; CD34 gene; Cell physiology; Cell surface; Cells; Chemotaxis; Collagen; Disease; Exhibits; Fibroblasts; Fibrosis; Gelatinase B; Goals; Hamman-Rich syndrome; Human; ITGAM gene; In Vitro; Inflammation; Inflammatory; Length; Lung; Lung diseases; MAPK8 gene; Mus; Myofibroblast; PTPRC gene; Patients; Peptides; Phenotype; Play; Pneumonia; Population; Predisposition; Proteins; Reagent; Regulation; Resolution; Role; Scleroderma; Signaling Molecule; Smooth Muscle Actin Staining Method; Structure of parenchyma of lung; Surface; Tertiary Protein Structure; Testing; Transplantation; Work; Wound Healing; caveolin 1; cell type; chemokine receptor; cytokine; effective therapy; immune function; in vivo; lung injury; monocyte; mouse model; overexpression; peripheral blood; progenitor; receptor expression; research study; scaffold

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蛋白的细胞是常驻成纤维细胞。现在越来越多的证据表明，称为纤维细胞的造血来源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为成纤维细胞。纤维细胞源自单核细胞，并表现出成纤维细胞（胶原）和单核细胞/造血表面标记。先前的研究强烈表明，caveolin-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，并导致从肺纤维化患者和对照受试者中分离的这些细胞之间的功能差异。这些研究（以及我们提出的研究）充分利用了 Caveolin-1 支架结构域 (CSD) 肽，当该肽合成为具有触角足内化序列的融合肽时，会进入细胞并模拟全长 Caveolin-1 的功能。主要观察结果是： 与对照受试者的相同细胞类型相比，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的 Caveolin-1 显着减少；硬皮病患者细胞中 Caveolin-1 表达的减少增加了信号分子的激活以及参与肺纤维化的几种蛋白质的表达，包括胶原蛋白、1-平滑肌肌动蛋白和 MMP-9；硬皮病单核细胞中的 Caveolin-1 表达减少可促进其分化为纤维细胞； CSD 肽体内治疗促进接受气管内博莱霉素的小鼠肺部炎症和纤维化的消退。这些观察结果有力地支持了这样的假设：单核细胞、纤维细胞和成纤维细胞中低水平的caveolin-1在IPF和硬皮病患者对肺纤维化的易感性中发挥着关键作用。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 Caveolin-1、ERK 和 JNK 对这些功能的调节； 2)确定CSD肽治疗对博莱霉素诱导的体内肺损伤/纤维化的有益作用是否涉及CSD肽对纤维细胞行为的影响。这些实验将使用移植了 EGFP+ 单核细胞和 EGFP+ 纤维细胞的小鼠进行。这些实验的结果将通过阐明 CSD 肽抑制动物模型（博来霉素治疗的小鼠）肺纤维化进展的机制，使我们更接近使用 CSD 肽或相关试剂治疗人类患者肺纤维化的目标。