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.

项目摘要 /摘要 受伤，手术或疾病期间伤口愈合受损会影响数百万患者 需要一年，并需要更好的治疗策略来增强组织修复。在皮肤中，修复 受伤之后涉及一系列事件，包括凝结，炎症，伤口 通过细胞增殖和迁移以及重新血管化和重塑闭合。通常， 该过程最终会随着疤痕而达到高潮，正常皮肤的再生未能发生。然而， 最近普及的伤口引起的头发新生成（Wihn）的模型，新的头发 卵泡和皮脂腺在大急性和燃烧伤口中再生，提供平台 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此过程的重要调节因子，并且是 参与炎症，伤口闭合和天然皮肤结构的再生。尽管 可溶性，生化因素，例如趋化因子，细胞因子和伤口的生长因子 人们认为环境可以调节其反应，对生物物理线索的了解少得不到 尽管细胞存在于富含的固体组织中，但仍调节其功能 机械提示。我们实验室和其他人的工作表明细胞外柔软 基质水凝胶可减少巨噬细胞炎症和肌纤维细胞激活。此外， 我们发现A机械激活和钙的渗透离子通道发挥作用 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 研究刚度和压电1在皮肤伤口愈合中的作用。在AIM 1中，我们将调查 刚度和压电1在鼠的伤口愈合中的作用全厚度皮肤伤口。在AIM 2中，我们 将使用Wihn模型检查刚度和压电在再生中的作用。一个 对细胞如何感知其机械环境的基本了解 伤口愈合可能会导致新的策略，以加快愈合并提高质量 修复的组织。