Cell migration and wound repair

细胞迁移和伤口修复

• 批准号: 10395418
• 负责人: Anna Huttenlocher
• 金额: $ 66.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395418
• 关键词: Affinity Chromatography; Autoimmune Diseases; Autoimmunity; Award; Biological Models; Cardiovascular Diseases; Cells; Complex; Cues; Defect; Diabetes Mellitus; Disease; Funding; Gene Expression; Goals; Health; Human; Imaging Device; Immunologic Deficiency Syndromes; Inflammation; Malignant Neoplasms; Mediating; Metabolism; Molecular; Optics; Pathologic; Process; Research; Research Personnel; Resolution; Ribosomes; Role; Signal Transduction; Tissues; Translating; Work; Wound models; Zebrafish; cell motility; cell type; chronic wound; design; diabetic; genetic manipulation; genome editing; human disease; microorganism interaction; migration; neutrophil; novel therapeutic intervention; repaired; response; tissue repair; transcriptome sequencing; wound healing

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.

抽象的 这项最大化研究者研究奖的续签申请的总体目标是了解 在伤口愈合过程中，单细胞和多细胞水平的复杂信号网络的整合。 尽管在理解指导伤口修复的信号方面进展，但仍有很大的差距 了解不同类型的细胞如何通信以整合伤口愈合反应。此差距限制 我们为广泛的人类疾病设计新的治疗策略的能力，包括糖尿病，癌症， 心血管疾病和自身免疫性。我们研究的总体重点是了解基本 调节细胞迁移以及细胞迁移缺陷的分子机制如何有助于 在组织损伤和修复的背景下人类疾病。遗传的光学透明度和易感性 操纵使斑马鱼成为剖析伤口期间多细胞和组织相互作用的理想模型系统 维修。在以前的资金期间，我们投入了大量精力来开发成像和 在伤口愈合过程中，操纵细胞动力学，细胞引导提示，代谢和基质重塑 简单而复杂的伤口模型。我们进行了大规模陷阱（翻译核糖体亲和力纯化） - RNASEQ并确定了上下文和细胞类型的特定基因表达变化。使用基因组编辑我们是 现在被中毒以发现调节中性粒细胞反向迁移的新信号传导机制和指导提示 和炎症分辨率，并影响伤口愈合过程中基质重塑。了解如何 伤口修复在单细胞和多细胞水平上进行了策划和整合，包括 微生物相互作用的作用，在不同类型的组织损伤中是我们未来研究的重点。 我们工作的总体目标是确定介导细胞迁移的关键信号网络和指导线索 在伤口修复期间，剖析病理状况如何改变它们，最终可能针对 了解和治疗人类疾病。