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

组织损伤反应是多细胞生物偶尔遇到敌人时必不可少的。 环境这些多组织反应包括上皮屏障修复（伤口愈合）、炎症和炎症。 感觉反应，如伤害性敏化。这些协调的反应共同修复组织 功能性和/或在其愈合时保护组织免受进一步损伤。我们的首要假设是， 组织修复生物学在多细胞生物体的进化早期就出现了。因此，许多 细胞策略、信号通路和动物用来感知和修复损伤的行为， 古老而又保守的物种发现基本的细胞生物学和遗传基础， 损伤诱导的反应是必不可少的。我们的长期目标是确定一整套细胞和基因， 启动和执行每一个组织损伤反应，并了解这些细胞和基因的功能， 共同协调受损组织的成功修复。我的实验室率先使用 果蝇幼虫研究胚后组织损伤反应，包括伤口闭合，炎症， 和损伤诱导的伤害性（疼痛）敏化。在MIRA资助的前四年，我们发现 伤口边缘粘附动力学的重要原理，发现了一条信号通路（与脊椎动物 血管内皮生长因子[VEGF]信号传导），其是炎性血细胞扩散所必需的。 伤口部位，并探讨损伤诱导的敏感性冷，化学和机械刺激。我们的工作 在未来五年内，将集中在这些先前研究中自然出现的三个关键问题上：1。如何 粘附连接蛋白（如β-连环蛋白）是否从伤口边缘去除，以及这种去除如何 影响其他伤口边缘反应，如肌动蛋白聚合？这个问题来自我们的观察 β-连环蛋白能迅速从伤口边缘的膜上清除使用我们以前开发的新工具 在此期间，我们处于非常有利的位置，可以在高度对称的伤口上实时成像这一过程， 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粘附在伤口上的在我们的第二个项目中，我们将探索这个关键， 问题和研究免疫细胞粘附/扩散和免疫细胞功能之间的关系， 伤口部位我们的最后一个项目将寻求确定关键的功能下游基因，介导急性 损伤诱导的伤害性敏化。这是我们对这一过程理解的一个重大空白，也是一个关键。 这是伤害性敏化研究中的一个问题。我的实验室在创造性的高影响力研究方面 对不同组织损伤反应的研究强烈表明，我们将继续取得原创性的进展， 发现，特别是如果我们正在进行的赠款写作负担是通过MIRA机制减轻。我们 该系统补充了该领域的其他系统，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/遗传水平上科普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.