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The Matricellular Protein CCN1 in Wound Healing

基质细胞蛋白 CCN1 在伤口愈合中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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
作者：
通讯作者：

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.)
影响因子：
0
作者：
Chaqour,Brahim;Grant,MariaB;Lau,LesterF;Wang,Biran;Urbanski,MateuszM;Melendez-Vasquez,CarmenV
通讯作者：
Melendez-Vasquez,CarmenV