F31 Microtubule function in the onset of whole-body regeneration

F31 微管在全身再生开始时的功能

• 批准号: 10607754
• 负责人: Xavier N Anderson
• 金额: $ 4.36万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607754
• 关键词: Adult; Animals; Anterior; Cell Differentiation process; Cell Maturation; Cells; Chemicals; Cicatrix; Data; Decapitation; Ectoderm; Endoderm; Event; Eye; Fluorescent in Situ Hybridization; Fresh Water; Gene Expression; Genes; Genetic Epistasis; Germ Layers; Goals; Growth; Head; Human; In Situ Hybridization; Injury; Instruction; Kinesin; Limb structure; Mammals; Mesoderm; Microtubules; Minus End of the Microtubule; Modeling; Molecular; Motor; Muscle; Muscle Cells; Muscle Fibers; Natural regeneration; Organ; Organism; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Planarians; Platyhelminths; Pluripotent Stem Cells; Process; Proteins; RNA Interference; Regenerative capacity; Regenerative pathway; Regenerative response; Regulation; Role; Signal Induction; Signal Transduction; Site; Specific qualifier value; Structure; Surgical Injuries; Surgical wound; Tail; Testing; Tissues; Transport Process; WNT Signaling Pathway; Wnt proteins; beta catenin; cell type; experimental study; eye formation; eye regeneration; inhibitor; injured; insight; neuronal cell body; novel; response; response to injury; restoration; small molecule; stem cells; stem-like cell; tissue regeneration; wound

Project Summary Tissue regeneration is the process of renewal, restoration and growth that allows an organism to re-grow limbs and organs after injury. Tissue regeneration abilities are present in diverse organisms, suggesting they may have been ancient, so the mechanisms controlling regeneration have been important to understand. The freshwater planarian flatworm Schmidtea mediterranea regenerates from nearly any surgical injury, including decapitation, and is a model for understanding the mechanistic basis of animal regeneration. After injury, tissue near wound sites signals to nearby adult pluripotent stem cells called neoblasts, which differentiate to replace all cell types of missing tissue. The highly conserved Wnt signaling pathway is essential for controlling regeneration of anterior-versus-posterior tissue identity in planarian regeneration. The earliest event in head versus tail determination is the injury induced expression of the secreted Wnt inhibitor notum selectively at anterior-facing and not posterior-facing wound sites. However, the mechanism directing this symmetry breaking event is unknown. Injury induced notum expression occurs from the soma of body wall muscle cells possessing longitudinally aligned muscle fibers, suggesting a role of muscle cell orientation and polarity in the onset of regeneration. However, the molecular signals and structure regulating this polarity are unknown, but classic small molecule inhibition studies in planaria suggest a possible role for microtubules in this process. The goal of this project is to uncover the mechanisms by which microtubules participate in the polarity of the regeneration response in the following specific aims. Aim 1 utilizes RNAi to test roles for microtubule regulatory factors expressed in muscle to control injury-induced gene expression at the onset of tissue regeneration. Aim 2 uses epistasis analysis with RNAi to uncover the mechanism by which a kinesin microtubule motor protein relates to a Wnt pathway for head and eye regionalization used in regeneration. These experiments will provide insight on the cellular and molecular mechanism of microtubules during injury induced regeneration. My results will provide new insights into understanding the other factors necessary for proper injury signal and help form a better understanding on what regulates polarity.

项目摘要 组织再生是更新，恢复和生长的过程，使生物可以重新生长 受伤后四肢和器官。组织再生能力存在于多种生物中，表明它们 可能是古老的，因此控制再生的机制很重要。这 淡水普拉纳利夫schmidtea地中海几乎因任何手术损伤而再生，包括 斩首，是理解动物再生机械基础的模型。受伤后，组织 靠近伤口部位的信号向附近的成年多能干细胞称为新元细胞，这些干细胞分化为替代所有 细胞类型缺失组织。高度保守的Wnt信号通路对于控制再生至关重要 平质再生中的前后组织身份。头部与尾巴最早的事件 确定是损伤诱导的分泌的Wnt抑制剂在前置的表达 而不是朝后伤口部位。但是，引导此对称破坏事件的机制是 未知。损伤引起的无体表达发生在拥有的体壁肌肉细胞的躯体中 纵向排列的肌肉纤维，表明肌肉细胞方向和极性在发作中的作用 再生。但是，调节这种极性的分子信号和结构尚不清楚，但是经典 平面中的小分子抑制研究表明，微管在此过程中可能起作用。目标 该项目是要揭示微管参与再生极性的机制 以下特定目的的响应。 AIM 1利用RNAi测试微管调节因子的作用 在组织再生开始时在肌肉中表达以控制损伤诱导的基因表达。 AIM 2用途 用RNAi分析的上毒分析，以发现驱动蛋白微管运动蛋白与 用于再生的头部和眼睛区域化的WNT途径。这些实验将提供有关 损伤期间微管的细胞和分子机制引起的再生。我的结果将提供 了解适当伤害信号所需的其他因素，并帮助形成更好的新见解 了解什么调节极性。