Immune and Genetic Controls of Tissue Regeneration in Mice and Humans

小鼠和人类组织再生的免疫和遗传控制

• 批准号: 10394124
• 负责人: Thomas H. Leung
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394124
• 关键词: Adoptive Transfer; Age; Aging; Animals; Architecture; Area; Blood; CXCR4 gene; Cardiovascular system; Cells; Chronic; Cicatrix; Clinical; Cytometry; Data; Diabetic Foot Ulcer; Ear; Ear Injury; Elderly; Endothelial Cells; Enhancers; Epidermis; Ethnic Origin; Exhibits; Fibroblasts; Fibrosis; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genomics; Health; Histone H3; Homologous Gene; Human; Hypertrophic Cicatrix; Immune; Immunophenotyping; Injury; Keloid; Learning; Lysine; Methods; Molecular; Molecular Biology; Mus; Natural regeneration; Nude Mice; Operative Surgical Procedures; Organ; Organoids; Parabiosis; Pathologic; Patients; Physiological; Quality of life; Serum; Signal Pathway; Single Nucleotide Polymorphism; Skin; System; Testing; Tissues; Translating; Trauma; Traumatic injury; Veterans; Wild Type Mouse; Work; age related; aged; base; cell type; decubitus ulcer; experimental study; functional disability; genomic locus; healing; improved; in vivo; injured; keratinocyte; loss of function; mouse genetics; mouse model; novel; novel therapeutic intervention; paracrine; promoter; receptor; recruit; regenerative; repaired; response to injury; skin color; skin fibrosis; skin wound; tissue regeneration; tissue repair; translational goal; wound; wound healing

Abstract/Summary Cutaneous wounds create significant health problems for Veterans, including wartime trauma, diabetic foot ulcers, pressure ulcers, and pathological scar formation. We aim to devise novel methods to stimulate self- repair mechanisms and to promote scar-less wound healing/full tissue regeneration in humans. We use a combination of loss-of-function mouse genetics, parabiosis (where the circulatory systems of two mice are surgically connected), mass cytometry, flow cytometry, genomics, lineage tracing, and molecular biology to study ear tissue regeneration in mice. Our prior work and current preliminary data demonstrate that in two different physiologic contexts, skin-secreted SDF1 regulates the switch between scar formation and tissue regeneration. In Aim 1, we will study how SDF1 promotes scarring and fibrosis. The canonical receptor for SDF1 is CXCR4. After injury, we hypothesize that skin-secreted SDF1 recruits CXCR4+ immune cells, which produce paracrine factors that induce fibroblasts to form fibrous tissue and scar. Recruited cell types will be defined and functionally tested. In Aim 2, we translate our findings directly into humans. While pathologic scar formation (keloids and hypertrophic scars) is more common in certain ethnicities, the genetic basis of keloid formation remains unknown. We hypothesize that increased SDF1 promotes formation of human pathologic scars. Indeed, human keloid tissue contains higher amounts of SDF1. We propose to identify single nucleotide polymorphisms in the SDF1 gene of keloid-prone and control patients. Identified polymorphisms will be introduced and functionally tested in an ex vivo human skin organoid system. This proposal seeks to understand how SDF1 regulates wound healing and tissue regeneration and to decipher the genetic basis for pathologic scar formation in humans.

摘要/概要 皮肤创伤会给退伍军人带来严重的健康问题，包括战时创伤、糖尿病足、 溃疡、压迫性溃疡和病理性瘢痕形成。我们的目标是设计新的方法来刺激自我- 修复机制和促进人类无疤痕伤口愈合/完全组织再生。我们使用一个 功能丧失小鼠遗传学、联体共生（其中两只小鼠的循环系统是 手术连接）、质谱仪、流式细胞仪、基因组学、谱系追踪和分子生物学， 研究小鼠耳组织再生。我们先前的工作和目前的初步数据表明，在两个 在不同的生理背景下，皮肤分泌的SDF 1调节瘢痕形成和组织增生之间的转换， 再生在目标1中，我们将研究SDF 1如何促进瘢痕形成和纤维化。典型的受体 SDF 1是CXCR 4。在损伤后，我们假设皮肤分泌的SDF 1募集CXCR 4+免疫细胞， 产生旁分泌因子，诱导成纤维细胞形成纤维组织和疤痕。招募的细胞类型将是 定义和功能测试。在目标2中，我们将我们的发现直接转化为人类。而病理性疤痕 瘢痕疙瘩的形成（瘢痕疙瘩和增生性瘢痕）在某些种族中更常见，瘢痕疙瘩的遗传基础 形成仍然未知。我们假设SDF 1的增加促进了人类病理性 伤疤事实上，人类瘢痕疙瘩组织含有更高量的SDF 1。我们建议鉴定单核苷酸 瘢痕疙瘩易感患者和对照患者SDF 1基因多态性。确定的多态性将 引入并在离体人皮肤类器官系统中进行功能测试。这项建议旨在 了解SDF 1如何调节伤口愈合和组织再生，并破译其遗传基础 病理性疤痕形成。