Chemical and Physical Mechanisms of Wound Detection

项目摘要 对损伤的快速检测和反应对于所有生物体的生存至关重要。在动物中，受伤的组织 必须迅速愈合并局部再生。伤口检测失败会导致急性和慢性疾病， 从愈合不良的伤口和感染到慢性皮肤发炎、纤维化和癌症。虽然exe- 伤口愈合的细胞机制（涉及细胞因子、生长因子等）已经被广泛研究， 其引发机制仍然知之甚少。我的目标是发展一种基因和生理上都健康的- 伤口检测的可行模型。对于伤口最初是如何形成的， 检测，以及第一伤口信号如何快速传输关于组织规模损伤的信息， 对远处的白细胞、上皮细胞和其他参与愈合的细胞的排斥。 我研究活斑马鱼的伤口检测，其伤口反应和免疫系统与哺乳动物相似， MALS还更适合于在高动物通过量下的高分辨率、实时成像。为此，我 实验室将定量活体成像与无偏计算图像分析和各种椎间盘间成像相结合， 从生物物理学到数学建模的基本方法。十多年来，我发现了三个 化学和一种物理伤口信号：过氧化氢（H2 O2）、细胞外ATP（eATP）、花生四烯酸 (AA)和核膜张力。这些发现在一个古老的领域引发了新的活动。然而，关键的机械- 目前仍存在一些研究空白：eATP是如何被感知来介导伤口快速闭合的，以及它是如何指导远处的细胞的 尽管它在组织中被迅速分解并且不能扩散到远离伤口的地方？H2 O2和AA 整合的信号来介导对伤口的快速炎症反应？伤口信号引起炎症-做 他们也解决了吗？在分子和细胞生物学水平上，创伤机械传导是如何调节的？ 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因子， tors.在接下来的五年里，对它们的研究可以为新的治疗方法铺平道路。 我在伤口信号方面的工作为其他生物学领域打开了大门，在这些领域，类似的机制可能 驱动医学上重要的过程，如感染反应、癌症和骨再生/重塑。 虽然我的小组的主要重点将仍然是早期伤口信号，我计划探索其中的一些 利用R35灵活的资助计划，开发新领域。

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.