Mechanisms of Tissue Morphogenesis in C. elegans

线虫组织形态发生机制

• 批准号: 9034587
• 负责人: Andrew D Chisholm
• 金额: $ 33.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034587
• 关键词: Actins; Address; Adult; Affect; Automobile Driving; Binding Proteins; Caenorhabditis elegans; Calcium; Calcium Signaling; Candidate Disease Gene; Cell physiology; Cells; Clinical; Complex; Cytoskeleton; DAP kinase; Data; Defect; Detection; Development; Diabetic ulcer; Environment; Epidermis; Epithelial; Epithelium; Family; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genetic screening method; Goals; Guanosine Triphosphate Phosphohydrolases; Healed; Health; Human; Hydrogen Peroxide; Hypertrophic Cicatrix; Injury; Keloid; Knowledge; Lasers; Lead; Life; Liquid substance; Mammals; Microtubules; Minus End of the Microtubule; Mitochondria; Modeling; Morphogenesis; Morphology; Nematoda; Opportunistic Infections; Organism; Orthologous Gene; Outcome; Pathology; Play; Process; Production; Puncture procedure; Reactive Oxygen Species; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Skin; System; Testing; Tissues; Tumor Suppressor Proteins; Vertebrates; Work; Wound Healing; Wound Repair Pathway; acute stress; antimicrobial peptide; base; cell injury; chronic wound; gene discovery; healing; in vivo; loss of function; mutant; novel; repaired; response; rho; screening; wound

 DESCRIPTION (provided by applicant): Wound healing is vital for the health and survival of multicellular organisms in their natural environment, and is of general biomedical significance. Skin wound healing in vertebrates involves the coordinated action of multiple tissues and cellular processes. Numerous signaling pathways have been implicated in the detection of and response to damage, yet major gaps exist in our knowledge of how such signals are triggered, integrated, and how they direct the diverse outcomes in wound repair in vivo. The overall goals of this project are to use the nematode C. elegans as a model for genetic and cellular analysis of epidermal wound repair. The adult C. elegans epidermis is a simple barrier epithelium that efficiently repairs puncture or laser wounds. Wounding triggers a set of epidermal responses including cytoskeletal rearrangements and induction of antimicrobial peptide transcription. Previous studies revealed a key role for calcium signaling in driving the cytoskeletal rearrangement in wound healing. This project will explore novel signaling mechanisms in C. elegans wound responses. We propose two specific aims. In Aim 1 the roles of mitochondrially generated reactive oxygen species (ROS) in wound-triggered signaling will be tested critically using a combination of candidate gene testing and forward genetic screens. Mutants displaying constitutively activated wound responses provide genetic mimics of the wound response and have allowed large-scale genetic screens to identify potential components of wound repair pathways. Such screens have revealed unanticipated roles for the microtubule cytoskeleton in wound repair. In Aim 2 the roles of microtubule dynamics regulators in wound repair in vivo will be assessed. The results of this research will lead to a better understanding of how epithelial repair processes operate in vivo to allow organisms to survive life threatening physical injuries. Key wound triggered signals such as calcium and ROS may play conserved roles in wound healing in many organisms, and results from these studies could inform our understanding of mechanisms of wound repair in mammals and humans

 描述（由适用提供）：伤口愈合对于自然环境中多细胞生物的健康和存活至关重要，并且具有一般的生物医学意义。脊椎动物的皮肤伤口愈合涉及多个时间和细胞过程的协调作用。在检测和对损伤的响应中，已经隐含了许多信号通路，但是在我们了解这种信号如何触发，整合的情况下以及它们如何直接在体内伤口修复中的潜水员结果中存在主要差距。该项目的总体目标是将线虫秀丽隐杆线虫用作表皮伤口修复的遗传和细胞分析的模型。成年秀丽隐杆线虫表皮是一种简单的屏障上皮，可有效维修穿刺或激光伤口。伤害会触发一组表皮反应，包括细胞骨架重排和诱导抗菌胡椒转录。先前的研究表明，钙信号传导在驱动伤口愈合中的细胞骨架重排方面起着关键作用。该项目将探索秀丽隐杆线虫伤口反应中的新型信号传导机制。我们提出了两个具体目标。在AIM 1中，将使用候选基因测试和正向基因筛选的组合对线粒体产生的活性氧（ROS）在伤口触发的信号传导中的作用进行批判性测试。表现出始终激活伤口反应的突变体提供了伤口反应的遗传模仿，并允许大规模的遗传筛选鉴定伤口修复途径的潜在成分。这样的筛选显示了微管细胞骨架在伤口修复中的意外作用。在AIM 2中，将评估微管动力学调节剂在体内伤口修复中的作用。这项研究的结果将使人们更好地了解上皮修复过程如何在体内运作，从而使生物可以生存威胁生命的身体伤害。关键的伤口触发信号（例如钙和ROS）在许多生物体中可能在伤口愈合中扮演保守的作用，而这些研究的结果可能会为我们对哺乳动物和人类伤口修复机制的理解提供信息