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.

项目概要 组织再生是更新、恢复和生长的过程，使有机体能够重新生长 四肢、脏器受伤后。组织再生能力存在于多种生物体中，这表明它们 可能很古老，因此了解控制再生的机制非常重要。这 淡水涡虫扁虫 Schmidtea mediterranea 几乎可以从任何手术损伤中再生，包括 斩首，是了解动物再生机制基础的模型。受伤后，组织 伤口附近向附近的成体多能干细胞（称为新生细胞）发出信号，这些细胞分化以取代所有 缺失组织的细胞类型。高度保守的Wnt信号通路对于控制再生至关重要 涡虫再生中的前部与后部组织同一性。头与尾的最早事件 测定是损伤诱导的分泌性 Wnt 抑制剂 notum 在前部选择性表达 而不是面向后的伤口部位。然而，引导这种对称性破缺事件的机制是 未知。损伤诱导的 notum 表达发生在具有 纵向排列的肌纤维，表明肌细胞方向和极性在肌纤维发生过程中的作用 再生。然而，调节这种极性的分子信号和结构尚不清楚，但经典 对涡虫的小分子抑制研究表明，微管在此过程中可能发挥作用。目标是 该项目旨在揭示微管参与再生极性的机制 响应以下具体目标。目标 1 利用 RNAi 测试微管调节因子的作用 在肌肉中表达以控制组织再生开始时损伤诱导的基因表达。目标2用途 利用 RNAi 进行上位分析，揭示驱动蛋白微管运动蛋白相关的机制 用于再生的头部和眼睛区域化的 Wnt 通路。这些实验将提供关于 损伤诱导再生过程中微管的细胞和分子机制。我的结果将提供 了解正确损伤信号所需的其他因素的新见解，并有助于形成更好的 了解调节极性的因素。