Innate immune regulation of wound re-epithelialization

伤口再上皮化的先天免疫调节

• 批准号: 10763642
• 负责人: Siqi Liu
• 金额: $ 24.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10763642
• 关键词: Affect; Aging; Atopic Dermatitis; Autoimmune; Biochemical; Biology; Carcinoma; Cell Death; Cell membrane; Cells; Chronic; Complex; Disease; Environment; Epidermis; Epithelium; Event; Family; Gene Expression Profiling; Genetic; Genetic Models; Goals; Growth Factor; Hair follicle structure; Host Defense; Immune; Immune signaling; Immune system; Immunology; Injury; Innate Immune System; Investigation; Knock-out; Knowledge; Ligands; Mechanics; Mediating; Mentors; Methods; Modeling; Molecular; Necrosis; Outcome; Pathology; Pattern; Pattern recognition receptor; Positioning Attribute; Process; Production; Proliferating; Psoriasis; Receptor Signaling; Research; Research Personnel; Role; Signal Induction; Signal Pathway; Signal Transduction; Site; Skin; Skin repair; Study Subject; T-Lymphocyte; Technical Expertise; Therapeutic; Tissues; Training; Transcriptional Activation; Trauma; Universities; adaptive immunity; adult stem cell; autoinflammatory; career development; cell injury; cytokine; diabetic ulcer; immune cell infiltrate; immunoregulation; improved; in vitro Assay; in vivo; injured; innate immune sensing; insight; keratinocyte; migration; non-healing wounds; novel; pathogen; recruit; repaired; response; skin wound; tissue regeneration; tool; transcription factor; wound; wound closure; wound healing; wound injury; γδ T cells

PROJECT SUMMARY/ABSTRACT Skin has a remarkable ability to heal wounds through re-epithelialization, a repair process fueled by adult stem cells residing in the epidermis and hair follicles. Following injury, wound-edge keratinocytes proliferate and migrate to initiate wound closure, which is accompanied by activation and infiltration of immune cells. My long-term goal is to elucidate the cellular and molecular basis underlying wound re-epithelialization, how the immune system regulates this process, and how it affects tissue regeneration. Previously we found activation of the transcription factor Stat3 in keratinocytes controls many important aspects of wound re-epithelialization, including basal keratinocyte proliferation, migration and crosstalk with epidermal dendritic T cells (DETCs). However, the molecular mechanism by which wounding triggers Stat3-mediated re-epithelialization and activates the immune system remains unclear and is the subject of this study. Cellular injury is known to produce damage associated molecular patterns (DAMPs) that are sensed by the innate immune system for host protection. We hypothesize that DAMPs produced by skin wounds are sensed by innate immune pattern recognition receptors (PRRs), which then signal to produce cytokines, and further activate Stat3 for wound re-epithelialization. Using a candidate approach and Stat3 activation as a readout, we will first identify, characterize, and verify wound-edge cytokines that influence wound re-epithelialization through epidermal-specific genetic knockouts, gene-expression analysis, and genetic modulation of immune signaling (Aim 1). Next, we describe strategies to identify the immune signaling pathway, upstream PRR, and the cells responsible for the PRR signaling through genetic and biochemical approaches (Aim 2). Finally, we describe an inducible genetic model of wound injury, characterize its similarity to physical wounding, and identify wound- induced ligands using biochemical purification and an in vitro assay (Aim 3). These lines of investigation will 1) offer novel insights into the molecular mechanism of wound initiation and innate immune contribution to skin re-epithelialization, 2) contribute new tools and models to the study of immune regulation and skin repair, and 3) improve our understanding and therapeutic options for autoimmune/autoinflammatory skin conditions and diseases associated with poor wound repair. With an exceptional mentoring team led by Dr. Elaine Fuchs (with Drs. Jean-Laurent Casanova and Daniel Mucida) and a supportive, stimulating training environment at the Rockefeller University, I am ideally positioned to fully develop my technical skills and knowledge in skin biology and immunology. My research, training, and career development will allow me to establish a unique niche in the field of wound-repair and tissue regeneration as an independent investigator.

项目总结/摘要 皮肤具有通过再上皮化来愈合伤口的显著能力，再上皮化是一种由以下因素推动的修复过程： 表皮和毛囊中的成体干细胞。受伤后，伤口边缘 角质形成细胞增殖并迁移以启动伤口闭合，这伴随着活化 以及免疫细胞的浸润我的长期目标是阐明 潜在的伤口再上皮化，免疫系统如何调节这一过程， 影响组织再生以前我们发现转录因子Stat 3在细胞内激活， 角质形成细胞控制伤口再上皮化的许多重要方面，包括基底 角质形成细胞增殖、迁移和与表皮树突状T细胞（DETC）的串扰。然而，在这方面， 创伤触发Stat 3介导的上皮再形成的分子机制， 激活免疫系统仍然不清楚，这是这项研究的主题。细胞损伤是 已知会产生损伤相关分子模式（DAMP），这些模式被先天性 免疫系统保护宿主。我们假设皮肤伤口产生的DAMP是 由先天免疫模式识别受体（PRRs）感知，然后发出信号， 细胞因子，并进一步激活Stat 3用于伤口再上皮化。使用候选人方法， Stat 3激活作为读数，我们将首先识别，表征和验证伤口边缘细胞因子， 通过表皮特异性基因敲除、基因表达 分析和免疫信号传导的遗传调节（Aim 1）。接下来，我们将描述一些策略， 识别免疫信号通路、上游PRR和负责PRR的细胞 通过遗传和生物化学方法进行信号传导（Aim 2）。最后，我们描述了一个诱导型 创伤损伤的遗传模型，表征其与物理创伤的相似性，并识别创伤- 使用生物化学纯化和体外测定诱导配体（Aim 3）。这几行 研究将1）提供新的见解伤口启动和先天的分子机制， 免疫对皮肤再上皮化的贡献，2）为研究 免疫调节和皮肤修复，以及3）提高我们对 自身免疫性/自身炎性皮肤病症和与不良伤口修复相关的疾病。与 由Elaine Fuchs博士领导的优秀指导团队（Jean-Laurent Casanova博士和丹尼尔博士 Mucida）和洛克菲勒大学的支持性，刺激性的培训环境，我是理想的 能够充分发展我在皮肤生物学和免疫学方面的技术技能和知识。我 研究，培训和职业发展将使我能够在该领域建立一个独特的利基 创伤修复和组织再生作为一个独立的研究者。