Chemical and Physical Mechanisms of Wound Detection

项目摘要 对伤害的快速检测和反应对所有生物体的生存至关重要。在动物身上，受伤的组织 必须迅速愈合并在局部再生。伤口检测失败会导致各种急性和慢性疾病 从愈合不良的伤口和感染到慢性发炎的皮肤、纤维化和癌症。尽管他的前任- 伤口愈合的治疗机制(涉及细胞因子、生长因子等)已经得到了广泛的研究， 其启动机制仍鲜为人知。我的愿景是发展出一种遗传和身体上的PLAU- 伤口检测的可行模型。对于伤口最初是如何形成的，在理解上存在着根本性的差距 以及第一创伤信号如何通过组织规模的分布快速传输关于损伤的信息。 转移到遥远的白细胞、上皮细胞和其他参与愈合的细胞。 我研究了活斑马鱼的伤口检测，这些斑马鱼的伤口反应和免疫系统与斑马鱼相似。 然而，在高动物吞吐量的情况下，雄性更容易接受高分辨率的实时成像。为此，我的 Lab将定量活体成像与无偏见的计算图像分析和各种间隙- 从生物物理学到数学建模的主要方法。十多年来，我已经确定了三个 化学和物理创伤信号：过氧化氢(H_2O_2)、细胞外ATP(EATP)、花生四烯酸 (Aa)和核膜张力。这些发现在一个老领域引发了新的活动。然而，关键的机甲- 反常的差距仍然存在：eATP是如何被感知来调节伤口的快速愈合的，以及它是如何指示遥远的细胞的？ 尽管它在组织中迅速分解，不能从伤口扩散得很远？过氧化氢和AA怎么样了？ 整合信号以调节对伤口的快速炎症反应？伤口信号引起炎症-DO 他们也解决了吗？创伤的机械转导在分子和细胞生物学水平上是如何调节的？ 这些问题具有很高的基础生物学意义，它们所涉及的途径是主要的疾病调节-- 托尔斯。在接下来的五年里回答这些问题可以为新的治疗方法铺平道路。 我在创伤信号方面的研究为生物学的其他领域打开了大门，在这些领域，类似的机制可能 推动医学上重要的过程，如感染反应、癌症和骨骼再生/重塑。 尽管我的团队的主要关注点仍然是早期创伤信号，但我计划探索其中的一些 新领域，利用R35‘S灵活的融资方案。

Project Summary Rapid detection and response to injury is essential for the survival of all organisms. In animals, wounded tissues must quickly heal and locally regenerate. Failure in wound detection causes acute and chronic conditions ranging from poorly healing wounds and infections to chronically inflamed skins, fibrosis and cancer. Although the exe- cution mechanisms of wound healing (involving cytokines, growth factors, etc.) have been extensively studied, its initiation mechanisms remain little understood. My vision is to develop a genetically and physically plau- sible model of wound detection. There is a fundamental gap in understanding of how wounds are initially detected, and how the first wound signals rapidly transmit information on injury over tissue-scale dis- tances to faraway leukocytes, epithelial, and other cells that participate in healing. I study wound detection in live zebrafish whose wound responses and immune system resemble those of mam- mals yet are better amenable to high-resolution, real-time imaging at high animal throughputs. To this end, my lab combines quantitative intravital imaging with unbiased computational image analysis and various interdisci- plinary approaches ranging from biophysics to mathematical modeling. Over a decade, I have identified three chemical and one physical wound signals: hydrogen peroxide (H2O2), extracellular ATP (eATP), arachidonic acid (AA), and nuclear membrane tension. These discoveries triggered new activity in an old field. Yet, critical mech- anistic gaps remain: How is eATP sensed to mediate rapid wound closure, and how does it instruct faraway cells although it is rapidly broken down in the tissue and cannot diffuse far from a wound? How are H2O2 and AA signals integrated to mediate rapid inflammatory responses to wounds? Wound signals cause inflammation- do they also resolve it? How is wound mechanotransduction regulated on the molecular and cell biological level? These questions are of high basic biological interest, and the pathways they concern are major disease regula- tors. Answering them over the next five years can pave way for novel therapeutic approaches. My work on wound signaling has opened the door to other areas of biology where analogous mechanisms may drive medically important processes, such as infection responses, cancer and bone regeneration/remodeling. Although the primary focus of my group will remain on early wound signaling, I plan to explore some of these new areas, taking advantage of the R35’s flexible funding scheme.