The Matricellular Protein CCN1 in Wound Healing

基质细胞蛋白 CCN1 在伤口愈合中的作用

• 批准号: 10170298
• 负责人: LESTER F LAU
• 金额: $ 40.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170298
• 关键词: Abscess; Amputation; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Apoptotic; Autophagocytosis; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Cell Aging; Cessation of life; Chronic; Clinical; Community-Acquired Infections; Complex; Diabetic mouse; Environment; Excision; Fibrosis; Generations; Gram-Negative Bacteria; Granulation Tissue; Hematogenous; Hospitals; Impaired wound healing; Impairment; Infection; Inflammation; Integrin Binding; Integrin alpha6beta1; Integrin alphaVbeta3; Invaded; Investigation; Knock-in Mouse; Lead; Mammals; Mediating; Methicillin Resistance; Microbe; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Natural Immunity; Nosocomial Infections; Opsonin; Organism; Phagocytes; Phagocytosis; Phase; Play; Process; Proteins; Pseudomonas aeruginosa; Quality of life; Reactive Oxygen Species; Resolution; Role; Sepsis; Skin wound healing; Staphylococcus aureus; Systemic infection; Testing; Therapeutic; Trauma; antibiotic resistant infections; base; cecal ligation puncture; chronic infection; chronic ulcer; chronic wound; cytokine; diabetic patient; diabetic ulcer; diabetic wound healing; healing; macrophage; microbial; mortality; mouse model; mutant; neutrophil; non-healing wounds; novel; novel strategies; novel therapeutic intervention; pathogen; polymicrobial sepsis; senescence; skin wound; tissue injury; wound; wound healing

PROJECT SUMMARY In an environment replete with microbial invaders, mammals must mount a successful defense against microbes in cutaneous wounds, trauma, and tissue injury. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria isolated from chronic skin wounds and among the most prominent pathogens in community-acquired and nosocomial infections, and these organisms readily develop antibiotic resistance. The matricellular protein CCN1 has recently emerged as an important multifunctional regulator of the wound healing process. CCN1 directly induces myofibroblast senescence through integrin α6β1 in the maturation phase of wound repair, thereby initiating matrix remodeling and dampening fibrosis. Recent studies have uncovered additional unexpected but critical activities of CCN1 in wound repair: (1) CCN1 acts as a bridging molecule and triggers the phagocytic removal of apoptotic neutrophils in wounds, resulting in resolution of inflammation and allowing healing to proceed. (2) CCN1 promotes clearance of S. aureus and P. aeruginosa by inducing their phagocytosis by macrophages and neutrophils. Bacterial clearance is impaired in knockin mice expressing a CCN1 mutant unable to bind integrin αvβ3/αvβ5, and accelerated in mice injected with purified CCN1 protein. Moreover, treatment of excisional wounds with purified CCN1 protein accelerates closure in diabetic mice. Based on these findings, we hypothesize that CCN1 is a multifunctional protein that regulates disparate aspects of wound healing, including clearance of infecting microbes, resolution of inflammation, and indirectly lead to enhanced granulation tissue formation. We will scrutinize this hypothesis in three specific aims: Aim 1 evaluates the role of CCN1 in bacterial clearance in animal models of infection; Aim 2 dissects the molecular mechanism of CCN1 action in bacterial clearance; and Aim 3 investigates how CCN1 accelerates diabetic wound healing. Together, these studies will illuminate the mechanism of a novel arsenal in innate immunity against microbial invaders and may prompt new approaches toward the management of antibiotic-resistant infections and chronic non-healing wounds.

项目摘要 在一个充满微生物入侵者的环境中，哺乳动物必须成功地抵御 皮肤伤口、创伤和组织损伤中的微生物。金黄色葡萄球菌和假单胞菌 铜绿假单胞菌是从慢性皮肤伤口分离的最常见的细菌， 在社区获得性感染和医院感染中的主要病原体，并且这些生物体容易 产生抗生素抗性。基质细胞蛋白质CCN 1最近已成为一种重要的 伤口愈合过程的多功能调节剂。CCN 1直接诱导肌成纤维细胞衰老 在创伤修复的成熟阶段通过整合素α6β1，从而启动基质重塑， 抑制纤维化。最近的研究发现了CCN 1在细胞内的其他意想不到但关键的活性。 创伤修复：（1）CCN 1作为桥接分子，触发细胞吞噬细胞清除凋亡的细胞因子， 中性粒细胞在伤口中，导致炎症的解决，并允许愈合进行。(2)CCN1 促进S.金黄色葡萄球菌和铜绿假单胞菌通过诱导它们被巨噬细胞吞噬作用， 中性粒细胞在表达CCN 1突变体的敲入小鼠中细菌清除受损， 整合素αvβ3/αvβ5，并在注射纯化CCN 1蛋白的小鼠中加速。此外，治疗 具有纯化的CCN 1蛋白的切除伤口加速糖尿病小鼠的闭合。根据这些发现， 我们假设CCN 1是调节伤口愈合的不同方面的多功能蛋白质， 包括感染微生物的清除，炎症的消退，并间接导致增强的 肉芽组织形成。我们将在三个具体目标中仔细研究这一假设：目标1评估 CCN 1在动物感染模型中细菌清除中的作用;目的2剖析其分子机制 CCN 1在细菌清除中的作用;目的3研究CCN 1如何加速糖尿病伤口 治愈总之，这些研究将阐明一种新的先天免疫武器库的机制， 微生物入侵者，并可能促使新的方法对管理耐药 感染和慢性不愈合伤口。

项目成果

Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis.

• DOI: 10.1002/hep4.2057
• 发表时间: 2022-10
• 期刊: Hepatology communications
• 影响因子: 5.1

CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation.

• DOI: 10.1038/s41467-022-30851-1
• 发表时间: 2022-06-03
• 期刊: Nature communications
• 影响因子: 16.6

Atomic Force Microscopy-Based Measurements of Retinal Microvessel Stiffness in Mice with Endothelial-Specific Deletion of CCN1.

基于原子力显微镜测量 CCN1 内皮特异性缺失的小鼠视网膜微血管硬度。

• DOI: 10.1007/978-1-0716-2744-0_22
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Chaqour,Brahim;Grant,MariaB;Lau,LesterF;Wang,Biran;Urbanski,MateuszM;Melendez-Vasquez,CarmenV
• 通讯作者: Melendez-Vasquez,CarmenV