Molecular and Cellular Mechanisms of Wound Repair

伤口修复的分子和细胞机制

• 批准号: 10657172
• 负责人: SUSAN M PARKHURST
• 金额: $ 46.56万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657172
• 关键词: Accidents; Actins; Actomyosin; Address; Biochemical; Biological; Biological Assay; Biological Process; Cell Survival; Cell membrane; Cell model; Cells; Cessation of life; Clinical; Complement; Complex; Cytokinesis; Cytoskeleton; Development; Discipline; Disease; Drosophila genus; Drug Delivery Systems; E-Cadherin; Embryo; Ensure; Event; Gene Family; Genes; Genetic; Genetic Screening; Goals; Homeostasis; Human; Image; Individual; Infection; Infection prevention; Injury; Integral Membrane Protein; Ion Channel; Lesion; Malignant Neoplasms; Mammalian Cell; Medical; Membrane; Molecular; Nature; Neoplasm Metastasis; Nuclear Envelope; Organ; Organism; Pathway interactions; Pattern; Physiological; Play; Positioning Attribute; Process; Proteins; Regenerative Medicine; Regulation; Research; Role; Rupture; Speed; Structure; Time; Tissues; Trauma; Work; Wound models; assault; cell cortex; cell injury; clinically relevant; daily functioning; environmental stressor; experience; experimental study; gene conservation; genetic approach; healing; imaging approach; improved; injury and repair; insight; interest; model organism; novel therapeutics; physiologic stressor; preservation; recruit; repair model; repaired; response; response to injury; seal; superresolution imaging; wound; wound closure; wound healing

PROJECT SUMMARY/ABSTRACT Most cells of the body experience physiological and environmental stresses during their normal daily functions that can lead to a ruptured cell cortex (plasma membrane and underlying cortical cytoskeleton). The capacity of cells to rapidly repair general daily injuries, as well as ones resulting from trauma, infection, or diseases/cancer, is essential for their survival. The general aim of this proposal is to delineate how cells deal with such cell cortex disruptions to efficiently and effectively repair the lesions. We have developed a robust inducible single cell repair model using the syncytial Drosophila embryo that has superb amenability for live imaging and genetic tractability that is unavailable in other cell wound repair models. Our repair model has allowed us to successfully employ global genetic approaches for the first time to delineate the outline of cellular events and to identify many required genes/gene families providing clear molecular entry points for investigating specific key steps in the repair process. Our long-term goal is to establish the molecular framework underpinning cell wound repair. The specific aims of this proposal are 1) to determine the means by which the membrane plug re-seals the torn plasma membrane then facilitates wound closure; 2) to determine how the actin ring is attached to the overlying plasma membrane to coordinate their actions as the wound is pulled closed; and 3) to elucidate the basis of cell cortex remodeling following wound closure. Our findings will impact our understanding of cell wound repair across phyla, complement work done in other cell repair models, provide new insights into key players/events needed for efficient repair, as well as how they work in concert to achieve successful wound closure, and contribute to our understanding of related fundamental cellular and developmental events. Our studies are also expected to be of significant medical relevance, as understanding the molecules, machineries, and pathways governing cell wound repair will be extremely valuable for developing new or enhancing existing strategies for treating cellular damage, and for disciplines such as regenerative medicine where cell based constructs are used to reconstruct tissues or clinical drug delivery systems where molecules cross cell membranes.

项目总结/摘要 身体的大多数细胞在正常的日常生活中都会经历生理和环境压力 这些功能可导致细胞皮层（质膜和下层皮层）破裂， 细胞骨架）。细胞快速修复一般日常损伤的能力，以及由 创伤、感染或疾病/癌症对他们的生存至关重要。本建议的总体目标是 描述细胞如何处理此类细胞皮质破坏，以高效且有效地修复 病变我们已经开发了一个强大的诱导单细胞修复模型使用合胞体果蝇 胚胎，具有极好的顺从性，为生活成像和遗传易处理性，这是不可用的，在其他 细胞创伤修复模型。我们的修复模型使我们能够成功地利用全球遗传 第一次描绘细胞事件的轮廓，并确定许多需要的方法， 基因/基因家族提供明确的分子切入点，以研究特定的关键步骤， 修复过程。我们的长期目标是建立支撑细胞创伤的分子框架 修复.该建议的具体目的是：1）确定膜塞 重新密封撕裂的质膜，然后促进伤口闭合; 2）确定肌动蛋白环如何 附着在上面的质膜上，以在伤口被拉合时协调它们的动作; 3）阐明创伤闭合后细胞皮质重塑的基础。我们的发现将影响 我们对跨门细胞创伤修复的理解，补充了在其他细胞修复模型中所做的工作， 为高效维修所需的关键参与者/事件以及他们如何在 音乐会，以实现成功的伤口愈合，并有助于我们了解有关 基本的细胞和发育事件。我们的研究也将具有重要意义 医学相关性，如了解控制细胞创伤的分子、机制和途径 修复对于开发新的或增强现有的治疗细胞损伤的策略将是极其有价值的。 损伤，以及再生医学等学科，其中基于细胞的构建体用于 重建分子穿过细胞膜的组织或临床药物输送系统。

项目成果

Prepatterning by RhoGEFs governs Rho GTPase spatiotemporal dynamics during wound repair.

• DOI: 10.1083/jcb.201704145
• 发表时间: 2017-12-04
• 期刊: The Journal of cell biology
• 作者: Nakamura M;Verboon JM;Parkhurst SM
• 通讯作者: Parkhurst SM

Rho family GTPase functions in Drosophila epithelial wound repair.

• DOI: 10.4161/21541248.2014.982415
• 发表时间: 2015
• 期刊: Small GTPases
• 作者: Verboon JM;Parkhurst SM
• 通讯作者: Parkhurst SM

Rho family GTPases bring a familiar ring to cell wound repair.

• DOI: 10.4161/21541248.2014.992262
• 发表时间: 2015
• 期刊: Small GTPases
• 作者: Verboon JM;Parkhurst SM
• 通讯作者: Parkhurst SM

Into the breach: how cells cope with wounds.

深入突破口：细胞如何应对伤口。

• DOI: 10.1098/rsob.180135
• 发表时间: 2018
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Nakamura,Mitsutoshi;Dominguez,AndrewNM;Decker,JacobR;Hull,AlexanderJ;Verboon,JeffreyM;Parkhurst,SusanM
• 通讯作者: Parkhurst,SusanM

Coordination of Rho family GTPase activities to orchestrate cytoskeleton responses during cell wound repair.

• DOI: 10.1016/j.cub.2013.11.048
• 发表时间: 2014-01-20
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Abreu-Blanco, Maria Teresa;Verboon, Jeffrey M.;Parkhurst, Susan M.
• 通讯作者: Parkhurst, Susan M.