Investigating the role of a conserved serine/threonine kinase, SAX-1, in higher-order dendrite pruning

研究保守丝氨酸/苏氨酸激酶 SAX-1 在高阶树突修剪中的作用

• 批准号: 10537345
• 负责人: Paola V Figueroa-Delgado
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-01-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537345
• 关键词: Actins; Adult; Afferent Neurons; Alleles; Binding; Biological; Biological Models; Brain; CXCL10 gene; Caenorhabditis elegans; Calcium Signaling; Cells; Cytoskeletal Modeling; Cytoskeleton; Defect; Dendrites; Development; Diapause; Disease; Dorsal; Down Syndrome; Drosophila genus; Ensure; Enzymes; Exposure to; Failure; Genes; Genetic; Genetic Screening; Goals; Image; Larva; Lead; Light; Link; Measures; Mediating; Microtubules; Molecular; Molting; Mus; Nematoda; Nervous system structure; Neurites; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Nuclear; Pathway interactions; Phosphotransferases; Process; Property; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Research; Research Proposals; Resolution; Role; Serine; Shapes; Signal Pathway; Signal Transduction; Sister; Suggestion; System; Testing; Threonine; Work; autism spectrum disorder; innovation; insight; labia; mutant; nervous system development; nervous system disorder; neural circuit; novel; protein protein interaction; recruit; reproductive development; response; scaffold

PROJECT SUMMARY Neurite remodeling is a highly conserved process that refines and establishes a mature nervous system. A failure in neurite remodeling leads to neurological and neurodevelopmental disorders. While developmental dendritic pruning, a means of neurite remodeling, has been extensively studied, the cell-biological mechanisms that control pruning remain poorly understood. Specifically, there is a fundamental gap in understanding how neurons can selectively prune specific dendritic branches while leaving sister branches intact. The long-term goal is to identify and understand the cell-biological mechanisms that direct branch-specific pruning. The nematode Caenorhabditis elegans inner labial 2 (IL2) neurons, upon entering a developmental diapause, extend a stereotypical dendritic arbor that is pruned when development is resumed – leaving primary dendrites intact. The stereotypic remodeling of IL2 neurons allows experimental access to elucidate the cell-biological mechanisms that confer selective pruning. The central hypothesis is that SAX-1, an evolutionarily conversed serine/threonine kinase, functions in a molecular pathway that links calcium signaling to cytoskeletal dynamics in higher-order dendrite branches to direct selective pruning. The rationale for this proposal is that studying the role SAX-1 during IL2 remodeling will offer a framework to understand how local regulation of the cytoskeleton confers branch-specific pruning. The central hypothesis will be tested by the following specific aims: 1) determine how SAX-1 directs pruning of higher-order IL2 dendrite branches; and 2) identify the genetic pathway in which SAX- 1 acts to regulate the cytoskeleton during pruning. The research proposal is innovative because it will 1) be the first to establish C. elegans as a model system for studying pruning, 2) elucidate a novel role for SAX-1 in dendritic pruning, and 3) determine how the cytoskeleton is locally regulated during pruning. The proposed research is significant because elucidating the fundamental cell-biological mechanisms of branch-specific pruning will significantly advance our understanding of developmental neurite remodeling. This understanding is a critical to inform us about how neurodevelopmental processes go awry in disorders such as Down Syndrome.

项目摘要 神经突重塑是一个高度保守的过程，可完善并建立成熟的神经系统。失败 在神经蛋白酶中，会导致神经和神经发育障碍。在开发树突状的同时 修剪是一种神经蛋白重塑的一种手段，已经广泛研究了细胞生物学机制 控制修剪仍然很少理解。具体而言，理解神经元的基本差距 可以选择性地修剪特定的树突分支，同时使姐妹分支完好无损。长期目标是 识别并了解直接分支特定修剪的细胞生物学机制。线虫 秀丽隐杆线虫内唇2（IL2）神经元进入发育滞育，延伸 恢复发育后修剪的定型树突阵列 - 使原发性树突完好无损。这 IL2神经元的刻板印象重塑允许实验访问以阐明细胞生物学机制 会议选择性修剪。中心假设是SAX-1，一种进化转换的序列/苏氨酸 激酶，在分子途径中起作用，该途径将钙信号传导与高阶细胞骨架动力学联系起来 树突分支以指导选择性修剪。该提议的理由是研究角色sax-1 在IL2重塑期间，将提供一个框架，以了解细胞骨架的局部调节 特定于分支的修剪。中心假设将通过以下特定目的测试：1）确定如何 SAX-1指导高阶IL2树突分支的修剪； 2）确定萨克斯 1在修剪过程中调节细胞骨架的作用。研究建议具有创新性，因为它将是1） 首先建立秀丽隐杆线虫作为研究修剪的模型系统，2）阐明SAX-1在 树突修剪和3）确定细胞骨架如何在修剪过程中局部调节。提议 研究很重要，因为阐明了分支特异性的基本细胞生物学机制 修剪将大大提高我们对开发神经重塑的理解。这种理解是 一个至关重要的信息，以告知我们神经发育过程如何在唐氏综合症等疾病中出现问题。