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

对于偶尔遇到敌意的多细胞生物来说，组织损伤反应是必不可少的 环境。这些多组织反应包括上皮屏障修复(伤口愈合)、炎症和 像伤害敏感化这样的感官反应。这些协调的反应共同恢复了组织 功能和/或在组织愈合时保护组织免受进一步损害。我们最重要的假设是 组织修复生物学在多细胞生物体进化的早期就出现了。因此，许多 动物用来感知和修复损伤的细胞策略、信号通路和行为是 古老的，进化上保守的。发现这些细胞的基本生物学和遗传基础 损伤诱导的反应是必不可少的。我们的长期目标是确定全套细胞和基因， 启动和执行每个组织损伤反应，并了解这些细胞和基因是如何发挥作用的 共同努力，成功修复受损组织。我的实验室已经率先使用了 研究胚胎后组织损伤反应，包括伤口闭合，炎症， 以及伤害诱导的伤害(痛)敏化。在我们米拉基金的头四年里，我们发现 伤口边缘粘连动力学的重要原理，发现了一条信号通路(与脊椎动物有关 血管内皮生长因子(血管内皮生长因子)信号转导)致炎血细胞在 伤口部位，并探索了伤害诱导的对寒冷、化学和机械刺激的敏感化。我们的工作 在接下来的五年里，我们将重点研究这些先前研究中自然出现的三个关键问题：1.如何 是否从伤口边缘去除黏附连接蛋白(如β-连环蛋白)？这种去除是如何进行的？ 影响其他伤口边缘反应，如肌动蛋白聚合？这个问题是从我们的观察中出现的 这种β-连环蛋白会迅速从伤口边缘的膜上移除。使用我们在上一阶段开发的新工具 在授权期内，我们处于一个极佳的位置，可以在高度对称的伤口和 以发现哪些信号通路协调移除。2.关于炎症的一个关键问题是 炎性血细胞最初是如何附着在伤口上的。在我们的第二个项目中，我们将探索这个关键 询问并研究免疫细胞黏附/扩散与免疫细胞功能的关系 伤口处。我们的最后一个项目将寻求识别关键的功能下游基因，这些基因介导急性呼吸道综合征 伤害诱导的伤害性敏化。这是我们对这一过程认识上的一个重大差距，也是一个关键 伤害性敏感化研究中的问题。我的实验室在创造性的高影响力研究方面的丰富历史 不同的组织损伤反应强烈地表明，我们将继续取得最初的进展，并 特别是如果通过MIRA机制减轻了我们正在进行的赠款编写负担的话。我们的 系统与该领域的其他系统相辅相成，并有可能继续对生物体如何进行新的基本见解 在细胞和分子/遗传水平上应对组织损伤的能力很高。

Tissue damage responses are essential for multicellular organisms that occasionally encounter a hostile environment. These multi-tissue responses include epithelial barrier repair (wound healing), inflammation, and sensory responses like nociceptive sensitization. Together, these coordinated responses restore tissue functionality and/or protect the tissue from further damage while it heals. Our overarching hypothesis is that the biology of tissue repair arose early in the evolution of multicellular organisms. Consequently, many of the cellular strategies, signaling pathways, and behaviors that animals use to sense and to repair damage are ancient and evolutionarily conserved. Discovery of the basic cell biology and genetic underpinnings of these damage-induced responses is essential. Our long term goal is to identify the full suite of cells and genes that initiate and execute each tissue damage response and understand how these cells and genes function and work together to orchestrate successful repair of damaged tissues. My laboratory has pioneered the use of Drosophila larvae to study postembryonic tissue damage responses including wound closure, inflammation, and injury-induced nociceptive (pain) sensitization. During our first four years of MIRA funding we discovered important principles of wound edge adhesion dynamics, found a signaling pathway (related to vertebrate Vascular Endothelial Growth Factor [VEGF] signaling) required for spreading of inflammatory blood cells at wound sites, and explored injury-induced sensitization to cold, chemical, and mechanical stimuli. Our work over the next five years will focus on three key questions that emerge naturally from these prior studies: 1. How are adherens junction proteins (like β-Catenin) removed from the wound edge and how does this removal impact other wound-edge responses like actin polymerization? This question emerges from our observation that β-Catenin is rapidly removed from wound-edge membranes. With new tools we developed in the prior grant period we are in an excellent position to image this process in real-time at highly symmetric wounds and to discover which signaling pathways coordinate removal. 2. One key question with respect to inflammation is how inflammatory blood cells initially adhere to the wound. In our second project we will explore this key question and investigate the relationship between immune cell adhesion/spreading and immune cell function at the wound site. Our final project will seek to identify key functional downstream genes that mediate acute injury-induced nociceptive sensitization. This is a major gap in our understanding of this process and a key question in the study of nociceptive sensitization. My lab’s substantial history of creative high-impact research on diverse tissue damage responses suggests strongly that we will continue to make original strides and discoveries, especially if our ongoing grant-writing burden is lessened through the MIRA mechanism. 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.