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: 10831130
• 负责人: VLADIMIR A BOTCHKAREV
• 金额: $ 40.62万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10831130
• 关键词: 3-Dimensional; Address; Adult; Affect; Aging; Animals; Biology; Biomedical Research; Blood Vessels; Boston; Candidate Disease Gene; Cardiovascular Diseases; Cell Communication; Cells; Chronic; Cicatrix; Clinic; Complex; Contracture; Data; Data Correlations; Defect; Deposition; Dermal; Development; Embryo; Epigenetic Process; Epithelium; Exhibits; Extracellular Matrix; Family suidae; Fibroblasts; Fibrosis; Gene Expression Profile; Genes; 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; Phase; Physiological; Physiology; Population; Prevention; Process; Proliferating; Rattus; Resistance; Rodent; Salamander; Secure; Signal Pathway; Signal Transduction; Skin; Skin graft; Skin injury; Skin repair; Skin wound healing; Study models; Testing; Tissues; Translations; Transplantation; Trauma; Universities; Vertebrates; age related; comparative; cost; epidermal stem cell; experimental study; genetic manipulation; genome analysis; healing; human disease; in vitro Model; in vivo; innovation; insight; keratinocyte; model organism; non-healing wounds; novel; novel therapeutic intervention; pharmacologic; 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.

项目总结 损伤后的皮肤修复是一个复杂的过程，需要常住皮肤之间的协调作用 细胞，招募免疫细胞，并导致局部组织沉积/重塑。创伤过程中细胞与细胞的相互作用 修复在几个水平上被调节，包括信号/转录因子介导的和表观遗传 虽然目前尚不清楚这些机制在病理性皮肤修复过程中是如何改变的。 增生性瘢痕通常发生在烧伤、创伤或手术后，其特征是 细胞外基质沉积，重塑不充分，导致严重的生理和 患者的心理问题。然而，有效的预防和治疗瘢痕是一种 组织损伤的结果仍然有限，至少部分是由于在翻译#年获得的数据方面的挑战。 不同的动物(小鼠、兔子、猪)模型给人皮肤和人皮肤留下疤痕。 现代生物医学研究的一个基本问题是寻找新的模式生物。 这充分反映了调节人类发展、动态平衡和老龄化的机制，以及它们的 人类疾病的变化。裸鼹鼠(NMRS)是一种独特的长寿哺乳动物 对癌症和其他与年龄相关的疾病具有显著的抵抗力，并保持持续的健康生活- 跨度长达32年，与小鼠或大鼠相比，这大约是十倍长。 比较基因组和转录组分析表明，核磁共振基因组具有较高的相似性 与小鼠和大鼠相比。我们的初步数据表明，NMRS还拥有 独特的再生皮肤伤口而不留下疤痕的能力，因此表明它们是独特的哺乳动物 预防成人皮肤损伤后瘢痕形成机制的研究模型。 在这项探索性拨款中，我们将检验一个假设，即核磁共振皮肤作为研究的独特模型。 伤口修复和疤痕形成的机制。这一假设将通过两个具体目标来解决(R61 在NMRS上获得的数据的相关性将在人体皮肤上进一步验证(R33阶段)。 R61阶段：目标1.将核磁共振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。确定有助于核磁共振皮肤无疤痕伤口愈合的机制。 R33阶段：目标3.验证控制瘢痕的不同调控机制的相关性- 在核磁共振皮肤到人皮肤的自由伤口修复过程中。 该应用程序生成的输出将提供对基本机制的新见解 损伤后潜在的疤痕形成，增强安全地建立一个地方的创新潜力 核磁共振作为研究人类皮肤生物学的模式生物，以及将促进 调节人类伤口愈合和疤痕形成的新范例。