Matrix Metalloproteinase Regulation of Leukocyte Infiltration during Wound Repair

伤口修复过程中基质金属蛋白酶对白细胞浸润的调节

• 批准号: 7987568
• 负责人: LISA Joy MCCAWLEY
• 金额: $ 30.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987568
• 关键词: Ablation; Adherence; Adhesions; Affect; Animals; Biological Assay; Biological Models; Bioreactors; Blood capillaries; Cell Line; Cell physiology; Chemotaxis; Clinical; Connective Tissue; Cytoskeleton; Endothelial Cells; Endothelium; Environment; Epidermis; Extravasation; Family; Family member; Fibroblasts; Genes; Goals; Growth Factor; Healed; Health; Host Defense; Hydrolysis; Immune; In Vitro; Individual; Infiltration; Inflammation; Leukocytes; MMP3 gene; MMP9 gene; MMPI; Maintenance; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Microfluidics; Modeling; Mus; Optics; Pattern; Peptide Hydrolases; Play; Population; Process; Regulation; Role; Site; Skin; Squamous cell carcinoma; Staging; System; Testing; Tissues; Transgenic Mice; Water; Wound Healing; adhesion receptor; base; capillary; cell type; defense response; design; fibrogenesis; healing; in vivo; in vivo Model; insight; keratinocyte; macrophage; member; migration; monocyte; monolayer; mouse model; neovascularization; neutrophil; novel; overexpression; prevent; public health relevance; response; tumor progression; wound

DESCRIPTION (provided by applicant): Upon loss of existing tissue integrity, wound closure is critical for maintenance of the protective epidermal barrier that shields the host from environmental insult and prevents water loss. An essential, initial response during wound repair is the influx of circulating leukocytes that cleanse the wound and also provide activators and growth factors to stimulate fibrogenesis and neovascularization. Members of the matrix metalloproteinase (MMP) family, such as MMP3, are potential key regulators of leukocyte infiltration. MMP3 is upregulated in the epidermis during processes undergoing tissue remodeling. Mice which are null for MMP3 have delayed closure of excisional wounds and demonstrate reduced infiltration of leukocytes in a number of model systems. Furthermore, we find that MMP3-/- animals have an increased sensitivity to SCC progression that is associated with a reduction in neutrophil and macrophage infiltration evident throughout all stages of tumor progression. Based upon these observations, we propose that MMP3 regulates a protective host defense response during wound repair that is reflective of a protective, antitumorigenic response during SCC. A number of molecules known to affect immune cell function can be directly targeted for hydrolysis and release by MMP3 or matrix proteinases which are activated by MMP3. We hypothesize that MMP3, in combination with other matrix proteinases, directly enhances leukocyte extravasation that subsequently influences the wound repair process. Leukocyte infiltration into sites of inflammation requires the coordinate regulation of multiple steps including arrest on endothelium, migration through the endothelial barrier and directed migration through connective tissue towards the site of inflammation. MMP3 is expressed by a variety of cell types including keratinocytes, fibroblasts, endothelial cells and monocytes and can activate other matrix proteinase classes; thus, MMP3 and other MMPs may modulate multiple key steps required for optimal leukocyte extravasation. The goal of this project is to elucidate the functional role of MMP3 in leukocyte extravasation during wound healing. Our specific aims will test our hypothesis as follows: Specific Aim 1: To identity the cellular matrix proteinase contributions of leukocytes, fibroblasts and keratinocytes to MMP3 dependent leukocyte infiltration into the wound environment using in vivo mouse models that are null for or have targeted overexpression of individual MMP family members. Specific Aim 2. To test the hypothesis that MMP3 activity regulates activation of subsequent MMP family members in wounded epidermis. Specific Aim 3: To identity the cellular mechanisms regulated during MMP3 and matrix protease dependent transendothelial migration in vitro. These studies will provide novel insights into the role of MMP3 and other matrix proteinases during leukocyte transendothelial migration and provide an in vivo model system for testing MMP inhibitors in a clinical setting. PUBLIC HEALTH RELEVANCE: Wounding of the skin requires healing to maintain normal health. An essential part of wound healing is inflammation. Matrix Metalloproteinases such as MMP3 may play a key role in regulating inflammation during wound healing.

描述（由申请人提供）： 在失去现有组织完整性后，伤口闭合对于维持保护性表皮屏障至关重要，该保护表皮屏障屏蔽了宿主免受环境损害并防止水分流失。伤口修复期间的必不可少的初始反应是清洁伤口的循环白细胞的涌入，还提供了激活剂和生长因子以刺激纤维发生和新血管形成。基质金属蛋白酶（MMP）家族（例如MMP3）的成员是白细胞浸润的潜在关键调节剂。在进行组织重塑过程中，在表皮中，MMP3在表皮中被上调。 MMP3无效的小鼠已延迟闭合裂解伤口，并显示许多模型系统中白细胞的浸润减少。此外，我们发现MMP3 - / - 动物对SCC进展的敏感性增加，这与肿瘤进展的所有阶段中明显的中性粒细胞和巨噬细胞浸润有关。基于这些观察结果，我们提出MMP3调节伤口修复过程中的保护性宿主防御反应，反映了SCC期间保护性的抗肿瘤反应。许多已知会影响免疫细胞功能的分子可以直接靶向水解和通过MMP3激活的MMP3或基质蛋白酶释放。我们假设MMP3与其他基质蛋白酶结合使用，直接增强了白细胞外渗，随后会影响伤口修复过程。白细胞浸润到炎症部位需要进行多个步骤调节，包括对内皮的逮捕，通过内皮屏障的迁移以及通过结缔组织迁移到炎症部位。 MMP3由多种细胞类型表达，包括角质形成细胞，成纤维细胞，内皮细胞和单核细胞，并可以激活其他基质蛋白酶类。因此，MMP3和其他MMP可能会调节最佳白细胞渗出所需的多个关键步骤。该项目的目的是阐明MMP3在伤口愈合过程中的白细胞渗出中的功能作用。我们的具体目的将检验我们的假设如下：具体目的1：为细胞基质蛋白酶的身份识别白细胞，成纤维细胞和角质细胞对MMP3依赖的白细胞渗透到伤口环境中，使用VIVO小鼠模型无效或对单个mmp family的靶向过度expractectionsefressions opersective摄入。具体目的2。测试MMP3活性调节受伤表皮中随后的MMP家族成员的激活的假设。特定目的3：在MMP3和基质蛋白酶依赖性跨内皮迁移过程中调节的细胞机制在体外。这些研究将提供有关白细胞跨内皮迁移过程中MMP3和其他基质蛋白酶作用的新见解，并为在临床环境中测试MMP抑制剂提供了体内模型系统。 公共卫生相关性： 皮肤伤口需要愈合才能保持正常健康。伤口愈合的重要组成部分是炎症。基质金属蛋白酶（如MMP3）可能在调节伤口愈合过程中的炎症中起关键作用。