Innate Immune Regulation of Wound Re-epithelialization

伤口上皮再生的先天免疫调节

• 批准号: 10266319
• 负责人: Siqi Liu
• 金额: $ 9.82万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266319
• 关键词: Affect; Aging; Atopic Dermatitis; Autoimmune Process; Biochemical; Biology; Carcinoma; Cell Death; Cell membrane; Cells; Chronic; Complex; Disease; Environment; Epidermis; Epithelial; 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; Knowledge; Ligands; Mechanics; Mediating; Mentors; Methods; Modeling; Molecular; Necrosis; Outcome; Pathology; Pattern; Pattern recognition receptor; Positioning Attribute; Process; Production; Proliferating; Psoriasis; Receptor Cell; Receptor Signaling; Research; Research Personnel; Research Training; Role; Signal Pathway; Signal Transduction; Site; Skin; Skin repair; Study Subject; T-Lymphocyte; Technical Expertise; Therapeutic; Tissues; Training; Transcriptional Activation; Trauma; Tumor-infiltrating immune cells; Universities; adaptive immunity; adult stem cell; autoinflammatory; career development; cell injury; cytokine; diabetic ulcer; immunoregulation; improved; in vitro Assay; in vivo; injured; innate immune sensing; insight; keratinocyte; knockout gene; 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.

项目摘要/摘要 皮肤具有通过再上皮化愈合伤口的非凡能力，这一修复过程由 成体干细胞存在于表皮和毛囊中。受伤后，伤口边缘 角质形成细胞增殖和迁移以启动伤口闭合，这伴随着激活。 以及免疫细胞的渗透。我的长期目标是阐明细胞和分子基础 潜在的伤口再上皮化，免疫系统如何调节这一过程，以及它是如何 会影响组织再生。之前我们发现转录因子STAT3在 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 角质形成细胞的增殖、迁移和与表皮树突状T细胞(DETCs)的串扰。然而， 创伤触发STAT3介导的再上皮化的分子机制 激活免疫系统的作用尚不清楚，这是本研究的主题。细胞损伤是 已知会产生损伤相关的分子模式(潮湿)，由先天感知 保护宿主的免疫系统。我们假设皮肤创伤产生的湿气 由先天免疫模式识别受体(PRR)感知，然后发出信号产生 细胞因子，并进一步激活STAT3以促进伤口再上皮化。使用候选方法和 STAT3激活作为读数，我们将首先识别、表征和验证创伤边缘细胞因子 表皮特异性基因敲除、基因表达对创面再上皮化的影响 免疫信号的分析和遗传调节(目标1)。接下来，我们将描述以下策略 确定免疫信号通路、上游PRR以及负责PRR的细胞 通过遗传和生化方法发出信号(目标2)。最后，我们描述了一个可诱导的 创伤的遗传模型，表征其与物理创伤的相似性，并识别创伤- 使用生化纯化和体外实验诱导配体(目标3)。这些产品线 研究将1)为伤口起始和先天的分子机制提供新的见解 免疫对皮肤再上皮化的贡献，2)为研究皮肤再上皮化提供了新的工具和模型 免疫调节和皮肤修复，以及3)提高我们对 自体免疫/自体炎症皮肤状况和与伤口修复不良相关的疾病。使用 由Elaine Fuchs博士(Jean-Laurent Casanova博士和Daniel博士)领导的卓越指导团队 穆奇达)和洛克菲勒大学一个支持性的、激动人心的训练环境，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。我的 研究、培训和职业发展将使我在以下领域建立独特的利基市场 伤口修复和组织再生作为独立的调查者。

项目成果

Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories.

• DOI: 10.1126/science.abh2444
• 发表时间: 2021-11-26
• 期刊: Science (New York, N.Y.)
• 作者: Gonzales KAU;Polak L;Matos I;Tierney MT;Gola A;Wong E;Infarinato NR;Nikolova M;Luo S;Liu S;Novak JSS;Lay K;Pasolli HA;Fuchs E
• 通讯作者: Fuchs E