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
• 负责人: ELENA TOURKINA
• 金额: $ 33.19万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369455
• 关键词: Actins; Address; Adverse effects; Affect; Amino Acids; Animal Model; Animals; Binding; Biological Models; Bleomycin; Blocking Antibodies; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Breathing; CD14 gene; CXCL12 gene; CXCR4 gene; Caring; Cause of Death; Cell physiology; Cell surface; Cells; Cessation of life; Collagen; Complex; Cytokine Signaling; Cytoskeleton; Development; Disease; Disease model; Epithelial Cells; FDA approved; Family; Fibroblasts; Fibrosis; GTP-Binding Proteins; Goals; Hamman-Rich syndrome; Hematopoietic; Hospitalization; Human; In Vitro; Individual; Infiltration; Interstitial Lung Diseases; Length; Ligand Binding; Ligands; Lung; Lung diseases; MAP Kinase Gene; Mediating; Medical; Modeling; Mus; Organ; PTPRC gene; Pathogenesis; Pathology; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Prevalence; Production; Proteins; Quality of life; Regulation; Reporting; Role; Scleroderma; Shapes; Shortness of Breath; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure of parenchyma of lung; Systemic Scleroderma; TLR4 gene; Tertiary Protein Structure; Testing; Tissues; Transitional Cell; Work; bone cell; caveolin 1; cell motility; cell type; chemokine receptor; effective therapy; genetic regulatory protein; human disease; improved; in vivo; indium-bleomycin; lung injury; migration; monocyte; neutrophil; novel; overexpression; progenitor; receptor; receptor function; receptor internalization; research study; response; scaffold; skin disorder; toll-like receptor 4; trafficking

DESCRIPTION (provided by applicant): Our long-term goal is to improve patient care in scleroderma and other interstitial lung diseases involving lung injury/fibrosis. While scleroderma is frequently thought of as a skin disease, in most patients it spreads to the lungs and other internal organs. This lung disease is devastating, results in a poor quality of life, is the most frequent cause of death in scleroderma, and has no FDA-approved treatment. Studies on lung tissue and blood cells from human patients and from animal lung disease model systems indicate that a common feature of interstitial lung diseases is the under expression in several cell types of caveolin-1, a protein that acts as a master regulator of several signaling pathways. It is particularly intriguing that both monocytes and fibroblasts are deficient in caveolin-1 because a portion of the fibroblasts present in fibrotic tissues are derived from bone marrow progenitors via the Bone Marrow Cell -> Monocyte -> Fibrocyte -> Fibroblast lineage. The identification of caveolin-1 as a key target in interstitial lung disease was validated using the caveolin-1 scaffolding domain (CSD) peptide, a peptide which mimics the function of full-length caveolin-1. In particular, CSD inhibits the overexpression of the chemokine receptor CXCR4 by scleroderma monocytes and their extremely active migration toward the CXCR4 ligand CXCL12. In vivo in the mouse bleomycin model system, CSD inhibits fibrosis, the overexpression of CXCR4 by monocytes, and monocyte and fibrocyte infiltration into damaged lung tissue. In summary, these observations suggest the hypothesis that a major role for caveolin-1 in the pathogenesis of interstitial lung diseases is in the regulation of CXCR4 expression, function in cell migration, and signaling in cells of the bone marrow -> monocyte -> fibrocyte lineage. To test this idea, we will: 1) Determine the mechanisms through which caveolin-1 regulates CXCR4 levels, function, and signaling and thereby regulates the trafficking of monocytes and fibrocytes; 2) Determine whether CXCR4/CD14/TLR4 receptor complexes differ in prevalence and function in Normal and SSc monocytes and the role of caveolin-1 in complex formation and function; and 3) Perform in vivo experiments to: Determine the function of caveolin-1 in regulating the trafficking of bone marrow-derived cells to the lungs via the blood and their phenotype and function, and to Promote the development of CSD as a drug for human patients. These studies will provide important, novel mechanistic details on the regulation by caveolin-1 of the function of cells in the fibrocyte lineage which play central roles in fibrotic diseases of the lungs and other organs. This information will further validate CSD as a novel treatment for these currently untreatable diseases and justify studies developing this treatment. This is of the utmost urgency because there are currently no effective treatments for scleroderma and other interstitial lung diseases. PUBLIC HEALTH RELEVANCE: There are no effective treatments for the several, frequently fatal, human diseases in which stiffening of lungs makes breathing difficult. A protein (caveolin-1) is deficient in several cell types in mice and humans with these diseases and can be replaced by treating cells or animals with a drug called CSD, resulting in the blockage of disease pathology. Here we address how the lack of caveolin-1 in blood cells called monocytes increases their expression of a protein called CXCR4 and thereby causes their migration into damaged lung tissue and their sequential conversion into cells called fibrocytes and fibroblasts that overexpress collagen resulting in the stiffening of lung tissue.

描述（由申请人提供）：我们的长期目标是改善硬皮病和其他涉及肺损伤/纤维化的间质性肺病的患者护理。虽然硬皮病通常被认为是一种皮肤病，但在大多数患者中，它会扩散到肺部和其他内脏器官。这种肺部疾病是毁灭性的，导致生活质量差，是硬皮病中最常见的死亡原因，并且没有FDA批准的治疗方法。对来自人类患者和动物肺病模型系统的肺组织和血细胞的研究表明，间质性肺病的共同特征是小窝蛋白-1（caveolin-1）在几种细胞类型中的表达不足，小窝蛋白-1是一种充当几种信号传导途径的主调节剂的蛋白质。特别令人感兴趣的是，单核细胞和成纤维细胞都缺乏小窝蛋白-1，因为纤维化组织中存在的一部分成纤维细胞经由骨髓细胞->单核细胞->纤维细胞->成纤维细胞谱系衍生自骨髓祖细胞。使用小窝蛋白-1支架结构域（CSD）肽（一种模拟全长小窝蛋白-1功能的肽）验证了小窝蛋白-1作为间质性肺病关键靶标的鉴定。特别地，CSD抑制硬皮病单核细胞对趋化因子受体CXCR 4的过表达以及它们向CXCR 4配体CXCL 12的极其活跃的迁移。在小鼠博来霉素模型系统中，CSD抑制纤维化、单核细胞CXCR 4的过表达以及单核细胞和纤维细胞浸润到受损的肺组织中。总之，这些观察结果表明了这样的假设，即小窝蛋白-1在间质性肺病发病机制中的主要作用是调节CXCR 4表达、细胞迁移功能和骨髓-单核细胞-纤维细胞谱系细胞中的信号传导。为了测试这个想法，我们将：1）确定小窝蛋白-1调节CXCR 4水平、功能和信号传导并从而调节单核细胞和纤维细胞的运输的机制; 2）确定CXCR 4/CD 14/TLR 4受体复合物在正常和SSc单核细胞中的流行率和功能是否不同，以及小窝蛋白-1在复合物形成和功能中的作用;和3）进行体内实验以：确定小窝蛋白-1在调节骨髓源性细胞通过血液向肺部运输中的功能 及其表型和功能，并促进CSD作为人类患者药物的发展。这些研究将提供关于小窝蛋白-1调节纤维细胞谱系中的细胞功能的重要的、新颖的机制细节，所述纤维细胞谱系在肺和其他器官的纤维化疾病中起核心作用。这些信息将进一步验证CSD作为这些目前无法治疗的疾病的新治疗方法，并证明开发这种治疗方法的研究是合理的。这是最紧迫的，因为目前还没有有效的治疗硬皮病和其他间质性肺病。 公共卫生关系：目前还没有有效的治疗方法来治疗几种经常致命的人类疾病，其中肺部硬化导致呼吸困难。一种蛋白质（小窝蛋白-1）在患有这些疾病的小鼠和人类的几种细胞类型中缺乏，可以通过用一种名为CSD的药物治疗细胞或动物来替代，从而阻断疾病病理。在这里，我们解决了在称为单核细胞的血细胞中缺乏小窝蛋白-1如何增加其称为CXCR 4的蛋白质的表达，从而导致其迁移到受损的肺组织中，并依次转化为称为纤维细胞和成纤维细胞的细胞，这些细胞过度表达胶原蛋白，导致肺组织硬化。