The skin of naked mole rats as a model for scar-free wound healing

裸鼹鼠皮肤作为无疤痕伤口愈合模型

• 批准号: 10238154
• 负责人: VLADIMIR A BOTCHKAREV
• 金额: $ 38.98万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238154
• 关键词: 3-Dimensional; Address; Adult; Affect; Aging; Animal Model; Animals; Biology; Biomedical Research; Blood Vessels; Boston; Burn Trauma; Candidate Disease Gene; Cardiovascular Diseases; Cell Communication; Cells; Chronic; Cicatrix; Clinic; Complex; Contracture; Data; Defect; Deposition; Dermal; Development; Embryo; Epigenetic Process; Epithelial; Exhibits; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression Profile; Genome; Grant; Growth; Hemostatic function; Heterocephalus; Homeostasis; Human; Human Biology; Human Development; Human Genome; Hypertrophic Cicatrix; Hypoxia; Immune; Inflammation; Injury; Keloid; Laboratories; Lentivirus; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mechanics; Mediating; Mesenchymal; Mesenchyme; Modeling; Modernization; Mole Rats; Mus; Natural regeneration; Nerve Degeneration; Nude Mice; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Output; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phase; Physiological; Physiology; Population; Prevention; Process; Proliferating; Rattus; Resistance; Rodent; Salamander; Secure; Signal Transduction; Signaling Protein; Skin; Skin graft; Skin injury; Skin repair; Skin wound healing; Study models; Testing; Tissues; Translations; Transplantation; Universities; Vertebrates; age related; base; comparative; cost; epidermal stem cell; experimental study; genome analysis; healing; human disease; in vitro Model; in vivo; innovation; insight; keratinocyte; non-healing wounds; novel; novel therapeutic intervention; porcine model; prevent; psychologic; recruit; repaired; single-cell RNA sequencing; skin regeneration; skin wound; stem cells; tissue injury; tissue repair; tool; transcription factor; transcriptome; tumorigenesis; wound; wound healing

PROJECT SUMMARY Skin repair after injury is a complex process that requires coordinate interactions between resident skin cells, recruited immune cells and result in local tissue deposition/remodeling. Cell-cell interactions during wound repair are regulated at several levels including signaling/transcription factor-mediated and epigenetic mechanisms, while it remains unclear how these mechanisms are altered during pathological skin repair. Hypertrophic scars commonly occur after burn, trauma or surgery, and are characterized by the excessive deposition of extracellular matrix with the inadequate remodeling, which result in severe physiological and psychological problems in patients. However, the effective prevention and treatment of the scars occurring as a result of tissue injury are still limited, at least in part, due to the challenges in translation of the data obtained in different animal (mouse, rabbit, pig) models to human skin and human skin scarring. One of the fundamental questions in modern biomedical research is the search for new model organisms that adequately reflect the mechanisms regulating human development, homeostasis and aging, as well as their alterations in human diseases. Naked mole rats (NMRs, Heterocephalus glaber) are unique long-lived mammals that possess marked resistance to cancer and other age-related pathologies and maintain sustained healthy life- span span for up to 32 years, which is approximately ten-fold longer compared to mice or rats. Comparative genome and transcriptome analyses revealed that the NMR genome show higher similarity to the human genome compared to mice and rats. Our preliminary data demonstrate that NMRs also possess the unique ability to regenerate skin wounds without scarring, thus suggesting them as the unique mammalian model for studying mechanisms preventing scar formation after injury in adult skin. In this exploratory grant, we will test a hypothesis that NMR skin serve as a unique model for studying mechanisms of wound repair and scar formation. This hypothesis will be addressed via two Specific Aims (R61 phase) and relevance of the data obtained on NMRs will be further validated on human skin (R33 phase). R61 phase: Aim 1. Characterize the NMR skin as innovative model for studying mechanisms of skin regeneration and wound healing. R61 phase: Aim 2. Define mechanisms contributing to scar-free wound healing in the NMR skin. R33 phase: Aim 3. Validate the relevance of distinct regulatory mechanisms controlling the scar- free wound repair process in the NMR skin to human skin. The generated outputs from this application will provide novel insights into fundamental mechanisms underlying scar formation after injury, enhance the innovative potential of securely establishing a place for the NMR as a model organism for studying the biology of human skin, as well as will promote the development of novel paradigms for modulation of wound healing and scar formation in humans.

项目摘要 损伤后的皮肤修复是一个复杂的过程，需要皮肤之间的协调相互作用 细胞、募集的免疫细胞并导致局部组织沉积/重塑。创伤过程中的细胞-细胞相互作用 修复在几个水平上受到调节，包括信号传导/转录因子介导的和表观遗传的 目前还不清楚这些机制在病理性皮肤修复过程中如何改变。 增生性瘢痕通常发生在烧伤、创伤或手术后，并且其特征在于过度的瘢痕化。 细胞外基质的沉积与不充分的重塑，这导致严重的生理和 患者的心理问题。然而，有效的预防和治疗作为一种 组织损伤的结果仍然是有限的，至少部分是由于在翻译中获得的数据的挑战， 不同的动物（小鼠、兔、猪）模型对人皮肤和人皮肤瘢痕的影响。 现代生物医学研究的基本问题之一是寻找新的模式生物 充分反映了调节人类发育、体内平衡和衰老的机制， 人类疾病的改变。裸鼹鼠（学名：Heterocephalus glaber）是一种独特的长寿哺乳动物 对癌症和其他与年龄有关的疾病具有显著的抵抗力，并保持持续的健康生活- 跨度跨度长达32年，与小鼠或大鼠相比大约长10倍。 比较基因组和转录组分析表明，NMR基因组显示出较高的相似性 与人类基因组相比。我们的初步数据表明，NMR还具有 独特的能力，再生皮肤伤口没有疤痕，从而表明他们作为独特的哺乳动物 用于研究防止成人皮肤损伤后瘢痕形成的机制的模型。 在这项探索性资助中，我们将测试一个假设，即核磁共振皮肤作为一种独特的模型，用于研究 创伤修复和瘢痕形成的机制。这一假设将通过两个具体目标（R61）来解决 阶段），并将在人体皮肤上进一步验证NMR上获得的数据的相关性（R33阶段）。 R61阶段：目标1。将NMR皮肤表征为研究皮肤机制的创新模型 再生和伤口愈合。 R61阶段：目标2。定义有助于NMR皮肤无疤痕伤口愈合的机制。 R33阶段：目标3。明确了控制瘢痕的不同调节机制的相关性， 在核磁共振皮肤的自由伤口修复过程中对人体皮肤。 该应用程序生成的输出将为基本机制提供新的见解 受伤后的潜在疤痕形成，增强了安全地为 核磁共振作为研究人体皮肤生物学的模式生物，以及将促进 用于调节人类伤口愈合和瘢痕形成的新范例。