The molecular and genetic bases of diverse tissue repair responses in postembryonic Drosophila

胚胎后果蝇不同组织修复反应的分子和遗传基础

• 批准号: 10374046
• 负责人: MICHAEL J GALKO
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374046
• 关键词: Biology; Blood Cells; Cell Shape; Cell fusion; Cells; Drosophila genus; Environment; Epigenetic Process; Epithelial Cells; Event; Funding; Genes; Genetic; Genetic Transcription; Goals; Grant; Inflammation; Inflammatory; Laboratories; Larva; Lead; Mediating; Molecular Genetics; National Institute of General Medical Sciences; Organism; Process; Publications; Recording of previous events; Signal Pathway; Signal Transduction; Site; Tissues; Vascular Endothelial Growth Factors; Veins; Work; Writing; base; cell behavior; cell motility; complement system; flexibility; functional restoration; gene function; healing; insight; interest; macrophage; migration; novel; programs; recruit; repair function; response; tissue repair; tissue-repair responses; transcription factor; wound; wound closure; wound healing; wound response

PROJECT SUMMARY/ABSTRACT Tissue repair is essential to multicellular organisms that occasionally encounter a hostile environment. The ability to rapidly repair and restore function to barrier tissues is critical to organismal survival and is highly conserved. My laboratory pioneered the use of Drosophila larvae to study postembryonic epidermal wound healing. Over the past eleven years (9 of them funded by R01GM083031; Genetic control of postembryonic wound healing in Drosophila) we have investigated the signaling mechanisms that initiate wound closure, that recruit inflammatory macrophage-like cells to the wound, that actually orchestrate wound-induced cell migration, and that mediate the curious phenomenon of wound-induced epidermal cell-cell fusion. This NIGMS R35 MIRA application is intended to provide more stable and flexible funding to my laboratory as it continues to pursue important cellular and mechanistic questions regarding organismal tissue repair responses. Our long- term goal is to identify the full suite of genes that initiate each important wound response (migration, cell shape change, dedifferentiation, fusion, inflammation) and understand how these genes function and work together to orchestrate a successful wound repair program. Our work over the next five years will focus on three essential questions that emerge naturally from our ongoing studies: 1. How does epigenetic reprogramming and a coordinated transcriptional response in wound edge cells help facilitate closure? This question emerges from our observation that some epigenetic regulators are cleared from wound edge cells and others, along with certain transcription factors, are directly required for wound closure. A major effort will be devoted to understanding the transcriptional and epigenetic changes that are necessary for healing at the wound edge. 2. We have now set up a viable platform for identifying and studying the function of genes that are necessary for the curious phenomenon of wound-induced cell-cell fusion. This effort is likely to lead to major novel insights into how the understudied process of epithelial cell-cell fusion is controlled and orchestrated. 3. How do blood cells adhere to and spread at a wound to serve their function of clearing cellular debris? We have now identified at least one signaling pathway (Vascular Endothelial Growth Factor [VEGF] signaling) that is required for blood cell spreading at wound sites. This suggests that attachment and spreading are genetically separable events and we have developed a strategy for both identifying more players in this process and studying the function of known players that act downstream of VEGF in this context. My lab's substantial history of creative high-impact publications on diverse aspects of tissue repair suggests strongly that we will continue in this vein, especially if our ongoing grant-writing burden is reduced. Our system complements others in the field and the likelihood of continued novel basic insight into how organisms cope with tissue damage at the cellular and molecular/genetic levels is high.

项目总结/摘要 组织修复对于偶尔遇到恶劣环境的多细胞生物至关重要。的 快速修复和恢复屏障组织功能的能力对生物体的生存至关重要， 保守的我的实验室率先使用果蝇幼虫来研究胚后表皮创伤 治愈在过去的11年里（其中9项由R 01 GM 083031资助;胚后发育的遗传控制）， 果蝇的伤口愈合），我们已经研究了启动伤口闭合的信号机制， 将炎性巨噬细胞样细胞募集到伤口， 迁移，并介导伤口诱导的表皮细胞-细胞融合的奇怪现象。这个NIGMS R35 MIRA申请旨在为我的实验室提供更稳定和灵活的资金，因为它继续 追求重要的细胞和机制问题，关于有机体组织修复反应。我们长久以来- 一个长期的目标是确定启动每一个重要的伤口反应（迁移，细胞形状）的全套基因 改变，去分化，融合，炎症），并了解这些基因如何发挥作用， 精心策划了一个成功的伤口修复计划今后五年，我们的工作重点将放在三个基本方面： 从我们正在进行的研究中自然出现的问题：1。表观遗传重编程和 伤口边缘细胞的协调转录反应有助于愈合？这个问题出现在 我们观察到一些表观遗传调节因子从伤口边缘细胞和其他细胞中清除，沿着 某些转录因子是伤口闭合所直接需要的。将作出重大努力， 理解伤口边缘愈合所必需的转录和表观遗传变化。2. 我们现在已经建立了一个可行的平台，用于识别和研究基因的功能，这些基因是必要的， 伤口引起的细胞融合的奇怪现象。这一努力很可能导致重大的新颖见解 深入研究上皮细胞间融合的过程是如何被控制和协调的。3.血液如何 细胞粘附并在伤口处扩散，以发挥其清除细胞碎片的功能？我们现在已经 确定了至少一种信号通路（血管内皮生长因子[VEGF]信号通路）， 血细胞在伤口处扩散这表明，依恋和传播在基因上是分离的 我们已经制定了一项战略，既确定更多的球员在这一进程中，并研究 在这种情况下，已知的作用于VEGF下游的参与者的功能。我的实验室有着丰富的创造性历史 关于组织修复的不同方面的高影响力的出版物强烈地表明我们将继续这方面的工作， 特别是如果我们正在进行的赠款写作负担减少。我们的系统补充了该领域的其他系统， 可能继续新的基本见解，生物体如何科普组织损伤的细胞和 分子/遗传水平很高。