Tissue mechanics in regenerative wound healing of the skin

皮肤再生伤口愈合中的组织力学

基本信息

批准号：
10217187
负责人：
Cheng-Ming Chuong
金额：
$ 31.35万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217187
关键词：
Accidents Acomys Adipose tissue Adult Age Ambystoma Amputation Atomic Force Microscopy Basement membrane Bioinformatics Biosensor C57BL/6 Mouse Cell Shape Cells Chemicals Cicatrix Connective Tissue Data Deposition Dermal Dermis Development Double-Stranded RNA Elements Embryonic Development Environment Epidermis Epigenetic Process Epithelial Epithelial Cells Event Excision Exhibits Extracellular Matrix FGF9 gene Fetus Fluorescence Resonance Energy Transfer Future Genes Genome Hair Hair follicle structure Inflammatory Response Intrinsic factor Knockout Mice Laboratories Laboratory mice Learning Maps Mechanics Modeling Molecular Mus Names Natural regeneration Nature Newborn Infant Outcome Patients Physical condensation Play Process Regenerative Medicine Regulation Role Signal Transduction Site Skin Skin wound healing Somatic Cell Spatial Distribution Testing Tissues Work appendage beta catenin blastema functional restoration healing improved mechanotransduction morphogens new therapeutic target novel progenitor programmed cell death protein 1 regenerative repaired reparative healing response shape analysis skin wound stem cells tissue regeneration tissue repair tongue papilla tumor wound wound bed wound closure wound environment wound healing wound treatment

项目摘要

Summary Our long term objective is to heal skin wounds with full functional restoration (regenerative wound healing) instead of scarring (reparative wound healing). We aspire to learn what factors control regeneration as supposed to repair during wound healing under the newly established paradigm of “Wound-Induced Hair Neogenesis” (WIHN). In this model, new hair follicles emerge from the wound center when a large (>1cm) skin wound is made on the mice (e.g., C57BL/6). Our new finding in Spiny mice (Acomys) shows, however, that WIHN starts to form from the periphery of wounds toward the center. Our preliminary data further shows a distinct spatial distribution of mechanical stiffness across the wound field, and that perturbation of mechanotransduction in the wound bed alters the outcome of WIHN. These new findings prompted us to hypothesize that tissue mechanics modulate tissue regeneration and WIHN. WIHN is easily accessible and is a good model to evaluate this hypothesis. While epithelial placode formation can be initiated by different chemical morphogens present during embryonic development (which converge to induce beta-catenin signaling), in WIHN of both C57BL/6 and spiny mouse, the mechanical environment of the wound can modulate, in parallel or independently, the threshold of successful placode formation. This acts to alter the status of epithelia activation, basement membrane remodeling, and dermal condensation. In Aim 1A, we will compare the different cellular and molecular events leading to WIHN, contrasting spiny and C57BL/6 mice. Supported by the bioinformatic analyses, Twist1 is proposed as a master regulator for placode formation in the spiny mouse. Therefore, the role of Twist1 and its downstream Msx2 in WIHN will be examined in Aim1B. In Aim 2A, we will map the stiffness in different parts of the wound field employing atomic force microscopy accompanied by cell shape analyses and FRET-biosensors to indirectly “visualize” the consequence of cell forces within the wound site. The role of tissue mechanics in WIHN will be further tested by perturbation studies. Aim 2B will investigate and define the molecular circuits which are functioning in the conductive mechanical environment for placode regeneration. Overall, the proposal aims to explore novel epidermal-dermal networks during regenerative wound healing from the perspective of epigenetic, molecular, and mechanical inputs that construct the grand theme of elements necessary for future progression of regenerative medicine. !

概括我们的长期目标是通过完整的功能恢复来治愈皮肤伤口（再生伤口愈合）而不是疤痕（修复性伤口愈合）。我们渴望学习哪些因素控制着在新近伤口愈合期间预期修复的预期再生的因素建立的“伤口引起的头发新发生”（Wihn）的范式。在这个型号中，新的头发当小鼠在大小（> 1厘米）的皮肤伤口上，从伤口中心出现卵泡（例如，C57BL/6）。我们在棘小鼠（ACOMYS）中的新发现表明，Wihn开始从奖金的外围向中心的外围形成。我们的初步数据进一步显示了机械刚度在整个伤口场的明显空间分布，以及扰动伤口床中的机械转导的变化改变了Wihn的结果。这些新发现促使我们假设组织力学调节组织再生和Wihn。 Wihn很容易访问，并且是评估这一假设的好模型。上皮可以由胚胎中存在的不同化学形态启动置换式形成开发（收敛到诱导β-catenin信号传导），在C57BL/6和刺小鼠，伤口的机械环境可以并联或独立地，成功的位置形成的阈值。这是为了改变状态上皮活化，基底膜重塑和真皮凝结。在AIM 1A中，我们将比较导致Wihn的不同细胞和分子事件，对比刺和 C57BL/6鼠。在生物信息学分析的支持下，提出了Twist1作为大师在刺中形成的调节剂。因此，Twist1及其作用 Wihn中的下游MSX2将在AIM1B中检查。在AIM 2A中，我们将绘制刚度使用细胞形状完成的原子力显微镜的伤口场的不同部分分析和对生物传动者间接地“可视化”细胞力在该内部的后果伤口部位。组织力学在Wihn中的作用将通过扰动研究进一步测试。 AIM 2B将调查并定义在导电中起作用的分子电路置换式再生的机械环境。总体而言，该提议旨在探索小说再生伤口愈合期间表皮 - 德法网络从构建元素主题的表观遗传学，分子和机械输入对再生医学的未来进展所必需的。呢