Regulation of wound detection in animal tissues

动物组织伤口检测的监管

基本信息

批准号：
9547881
负责人：
Philipp Michael Niethammer
金额：
$ 32.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9547881
关键词：
ATP Receptors Acids Affect Anti-inflammatory Binding Sites Biochemical Biochemistry Bioinformatics Biology Biosensor CRISPR/Cas technology Cardiovascular Diseases Cell surface Characteristics Chemicals Chemotactic Factors Connexins Couples Data Detection Disease Drug Targeting Eicosanoids Enzymes Epithelial Epithelial Cells Event Gene Deletion Genetic Grant Homeostasis Human Human Genome Hydrogen Peroxide Hydroxyeicosatetraenoic Acids Image Immune Infection Inflammation Inflammatory Injury Lead Leukocyte Chemotaxis Leukocytes Lipids Malignant Neoplasms Mammals Mediating Mediator of activation protein Modeling Molecular NADP NADPH Oxidase Orthologous Gene Oxidants Oxidoreductase Pathologic Phagocytes Pharmacology Physiological Physiology Production Proteins Purinoceptor Reaction Regulation Reporting Research Role Signal Transduction Time Tissues U937 Cells Wound Infection Zebrafish animal tissue cell motility clopidogrel experimental study extracellular in vivo intravital imaging knock-down migration new therapeutic target novel optical imaging oxidation paracrine receptor recruit repaired response tissue/cell culture wound wound closure

项目摘要

Project Summary Wounding of epithelial tissue barriers disrupts homeostasis and allows infection. Within minutes, tissues detect injury and respond by recruiting phagocytes and closing the barrier breach. The signals that activate these early events are scarcely known, and our overall aim is to identify them. We have used zebrafish, whose wound responses are close to mammals and easy to image and perturb with genetics and pharmacology, to define early wound signals. During the last grant cycle, we found that activation of Duox, an H2O2-producing NADPH-oxidase, and release of a lipid chemoattractant (5-KETE), together are required to attract leukocytes to epithelial wounds. The molecular mechanisms that integrate NADPH-oxidase activity with lipid chemoattractant production remain unclear. In parallel, we identified extracellular ATP (eATP) as crucial paracrine mediator of rapid wound closure through stimulating basal epithelial cell migration in vivo. The molecular mechanisms that convey ATP release and sensing to promote epithelial repair remain unclear. For the following grant cycle, I propose to investigate how Duox activity regulates lipid chemoattractant production, and how eATP is released and sensed in live tissues to mediate rapid epithelial repair. By combining real-time biosensor imaging in live zebrafish with genet- ics, bioinformatics, biochemistry and chemical biology approaches, we aim to identify and characterize elusive molecular key players of wound detection in vivo. Our research has strong potential to provide new drug targets for anti-inflammatory and anti-fibrotic therapy.

项目概要上皮组织屏障的损伤会破坏体内平衡并导致感染。几分钟之内，组织就会检测到损伤并通过招募吞噬细胞和关闭屏障缺口来做出反应。激活这些早期的信号事件鲜为人知，我们的总体目标是查明它们。我们用了斑马鱼，它的伤口反应接近哺乳动物，易于成像并通过遗传学和药理学进行干扰，以早期定义伤口信号。在上一个资助周期中，我们发现 Duox（一种产生 H2O2 的 NADPH 氧化酶）的激活，和脂质趋化剂（5-KETE）的释放共同需要将白细胞吸引到上皮伤口。将 NADPH 氧化酶活性与脂质趋化剂产生相结合的分子机制仍然存在不清楚。与此同时，我们发现细胞外 ATP (eATP) 是伤口快速闭合的关键旁分泌介质通过刺激体内基底上皮细胞迁移。传递 ATP 释放的分子机制促进上皮修复的传感和传感仍不清楚。对于接下来的拨款周期，我建议进行调查 Duox 活性如何调节脂质趋化剂的产生，以及 eATP 如何在活体中释放和感知组织介导快速上皮修复。通过将活体斑马鱼的实时生物传感器成像与基因相结合 ICS、生物信息学、生物化学和化学生物学方法，我们的目标是识别和表征难以捉摸的体内伤口检测的分子关键角色。我们的研究具有提供新药物靶点的强大潜力用于抗炎和抗纤维化治疗。