Mechanical regulation of skin repair and regeneration

皮肤修复和再生的机械调节

• 批准号: 10200676
• 负责人: Wendy Liu
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200676
• 关键词: Acute; Adipose tissue; Behavior; Biochemical; Biophysics; Blood coagulation; Calcium; Caliber; Cardiovascular Diseases; Cell Proliferation; Cell physiology; Cells; Chronic Disease; Cicatrix; Clinical; Coagulation Process; Collaborations; Cues; Disease; Environment; Event; Excision; Extracellular Matrix; Fibroblasts; Fibrosis; Goals; Growth Factor; Hair; Hair follicle structure; Hydrogels; Impaired healing; Impaired wound healing; Inflammation; Inflammatory; Injury; Ion Channel; Knowledge; Laboratories; Lead; Leucocytic infiltrate; Malignant Neoplasms; Mechanics; Modeling; Molecular; Molecular Target; Mus; Myofibroblast; Natural regeneration; Operative Surgical Procedures; Pathologic Processes; Patients; Permeability; Pharmacology; Phenotype; Piezo 1 ion channel; Play; Process; Regulation; Research; Role; Sebaceous Glands; Signal Transduction; Skin; Skin repair; Skin wound healing; Solid; Speed; Stimulus; Structure; Testing; Thick; Tissues; Traction; Vascularization; Work; Wound models; acute wound; burn wound; cell motility; chemokine; conditional knockout; cytokine; healing; immunoregulation; improved; insight; macrophage; mechanotransduction; mouse model; novel; novel therapeutic intervention; regenerative; repaired; response; response to injury; skin regeneration; skin wound; stem cell differentiation; tissue regeneration; tissue repair; treatment strategy; wound; wound closure; wound environment; wound healing

PROJECT SUMMARY / ABSTRACT Impaired wound healing after injury, surgery, or during disease impacts millions of patients each year, and better treatment strategies to enhance tissue repair are needed. In the skin, repair following injury involves a cascade of events that includes clotting, inflammation, wound closure via cell proliferation and migration, and re-vascularization and remodeling. Commonly, the process culminates with scarring, and regeneration of normal skin fails to occur. However, a recently popularized model for wound-induced hair neogenesis (WIHN), whereby new hair follicles and sebaceous glands regenerate in large acute and burn wounds, provides platform for studying how to modulate wound healing to promote more complete skin regeneration. Macrophages and fibroblasts are essential regulators of this process, and are involved in inflammation, wound closure, and regeneration of native skin structures. While soluble, biochemical factors such as chemokines, cytokines and growth factors in the wound environment are thought to regulate their responses, less is known about how biophysical cues regulate their function, despite the fact that cells exist within solid tissues that are rich in mechanical cues. Work from our laboratory and others have demonstrated that soft extracellular matrix hydrogels reduces macrophage inflammation and myofibroblast activation. Furthermore, we found that the a mechanically-activated and calcium permeable ion channel, plays a major role in mechanotransduction in both macrophages and fibroblasts. In this study, we propose to investigate role of stiffness and Piezo1 in skin wound healing. In Aim 1, we will investigate the roles of stiffness and Piezo1 on wound healing in murine full thickness skin wound. In Aim 2, we will examine the roles of stiffness and Piezo1 in regeneration using the WIHN model. An improved fundamental understanding of how cells sense their mechanical environment during wound healing may lead to new strategies that speed healing and enhance the quality of repaired tissue.

项目总结/摘要 受伤、手术后或疾病期间的伤口愈合受损影响了数百万患者， 需要更好的治疗策略来增强组织修复。在皮肤中，修复 损伤后会发生一连串的事件，包括凝血、炎症、伤口 通过细胞增殖和迁移以及再血管化和重塑来闭合。一般来说， 该过程以瘢痕形成而达到高潮，正常皮肤的再生不能发生。然而，在这方面， 最近流行的创伤诱导毛发新生（WIHN）模型， 毛囊和皮脂腺在大面积急性和烧伤伤口中再生， 用于研究如何调节伤口愈合以促进更完整的皮肤 再生巨噬细胞和成纤维细胞是这一过程的重要调节因子， 参与炎症、伤口闭合和天然皮肤结构的再生。而 伤口中的可溶性生物化学因子如趋化因子、细胞因子和生长因子 环境被认为可以调节它们的反应，但对生物物理线索如何影响它们的反应却知之甚少。 调节它们的功能，尽管事实上细胞存在于固体组织中， 机械提示我们实验室和其他人的工作表明， 基质水凝胶减少巨噬细胞炎症和肌成纤维细胞活化。此外，委员会认为， 我们发现，机械激活的钙离子通道，起着主要的作用， 在巨噬细胞和成纤维细胞中的机械转导中的作用。在这项研究中，我们建议 研究硬度和Piezo 1在皮肤伤口愈合中作用。在目标1中，我们将研究 硬度和Piezo 1在小鼠全层皮肤伤口愈合中的作用。在目标2中， 将检查的作用，刚度和Piezo 1再生使用WIHN模型。一个 提高了对细胞如何感知其机械环境的基本理解， 伤口愈合可能会导致新的策略，加速愈合和提高质量， 修复的组织