Cell migration and wound repair

摘要 此最大化调查员研究奖续展申请的总体目标是了解 在伤口愈合过程中，在单细胞和多细胞水平上整合复杂的信号网络。 尽管在理解指导伤口修复的信号方面取得了进展，但在 了解不同类型的细胞如何沟通以整合伤口愈合反应。这一差距限制了 我们有能力设计新的治疗策略来治疗包括糖尿病、癌症、 心血管疾病和自身免疫。我们研究的总体重点是了解基本的 调节细胞迁移的分子机制以及细胞迁移缺陷如何导致 人类疾病在组织损伤和修复的背景下。遗传的光学透明性和易用性 操作使斑马鱼成为解剖创伤过程中多细胞和组织相互作用的理想模型系统 修理。在之前的融资期间，我们投入了大量精力来开发新的成像工具和 在伤口愈合过程中操纵细胞动力学、细胞引导信号、代谢和基质重塑 简单创伤模型和复杂创伤模型。我们进行了大规模的TRAP(翻译核糖体亲和纯化)- RNAseq和已确定的上下文和细胞类型特定基因的表达变化。使用基因组编辑，我们正在 现在准备发现调节中性粒细胞反向迁移的新信号机制和指导信号 和炎症消退，并影响伤口愈合过程中的基质重塑。了解如何 创伤修复在单细胞和多细胞水平上都是协调和整合的，包括 微生物的相互作用，在不同类型的组织损伤中的作用是我们未来研究的重点。 我们工作的总体目标是确定调节细胞迁移的关键信号网络和指导线索 在伤口修复期间，解剖它们在病理条件下是如何改变的，并最终可能成为 了解和治疗人类疾病。

ABSTRACT The overall goal of this Maximizing Investigator’s Research award renewal application is to understand the integration of complex signaling networks at both the single cell and multi-cellular level during wound healing. Despite progress in understanding the signals that guide wound repair, there remains a significant gap in understanding how different types of cells communicate to integrate a wound healing response. This gap limits our ability to design new therapeutic strategies for a broad range of human disease including diabetes, cancer, cardiovascular disease and autoimmunity. The overall focus of our research is to understand the basic molecular mechanisms that regulate cell migration and how defects in cell migration contribute to human disease in the context of tissue damage and repair. The optical transparency and ease of genetic manipulation make zebrafish an ideal model system to dissect multi-cellular and tissue interactions during wound repair. During the prior funding period, we invested significant effort in developing new tools for imaging and manipulating cell dynamics, cell guidance cues, metabolism and matrix remodeling during wound healing in both simple and complex wound models. We performed large-scale TRAP (translating ribosomal affinity purification)- RNAseq and identified context- and cell-type specific gene expression changes. Using genome editing we are now poised to uncover new signaling mechanisms and guidance cues that regulate neutrophil reverse migration and inflammation resolution, and influence matrix remodeling during wound healing. Understanding how wound repair is orchestrated and integrated at both the single cell and multi-cellular level, including the role of microbial interactions, in the different types of tissue damage is the focus of our future research. The overall goal of our work is to identify key signaling networks and guidance cues that mediate cell migration during wound repair, dissect how they are altered in pathological conditions and ultimately may be targeted to understand and treat human disease.