Role of msps and tacc during axon guidance

msps 和 tacc 在轴突引导过程中的作用

• 批准号: 7876914
• 负责人: Laura Anne LOWERY
• 金额: $ 5.05万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876914
• 关键词: Actins; Address; Affect; Axon; Binding; Biochemical; Biological Assay; Cell Line; Cells; Cellular biology; Complex; Cues; Cytoskeletal Proteins; Cytoskeleton; Defect; Dissection; Drosophila genus; Embryonic Nervous System; Future; Genetic; Genetic Models; Genetic Screening; Goals; Growth Cones; Image; Inherited; Life; Light; Link; Logic; Malignant Neoplasms; Mediating; Microtubule-Associated Proteins; Microtubules; Modeling; Natural regeneration; Nerve Regeneration; Nervous system structure; Neurons; Ocular orbit; Pathway Analysis; Pathway interactions; Phenotype; Phosphotransferases; Play; Plus End of the Microtubule; Process; Protein Tyrosine Kinase; Proteins; Proteomics; Reporting; Research; Resolution; Role; Signal Transduction; Specificity; Testing; Therapeutic; Work; Xenopus; axon guidance; axonal pathfinding; extracellular; inhibitor/antagonist; mutant; nerve injury; nervous system development; nervous system disorder; neuron development; neuronal growth; prevent; protein protein interaction; receptor; therapy design

DESCRIPTION (provided by applicant): Accurate axon pathfinding is an essential yet highly complicated process during nervous system development. The mechanisms by which axons form complex functional neuronal networks are still a major puzzle and are relevant to understanding how abnormalities in neuronal development arise and also to nerve regeneration therapeutics. My long-term goal is to define the logic by which guidance information is integrated at the level of cytoskeletal dynamics control during axon pathfinding. As a starting point to address this issue, I will study the role of Msps and TACC, two microtubule-associated proteins which have been recently identified as suppressors of the Abl tyrosine kinase effector protein Orbit which regulates microtubule dynamics in the growth cone and mediates midline axon repulsion in the Drosophila nervous system. I will use genetic, biochemical, proteomic, and cell biological assays to investigate Msps, TACC and Orbit function in the growth cone to define the network of interactions which coordinate positive and negative microtubule dynamics during axon guidance. Specifically, I will: 1) define potential genetic pathways of interaction between Msps, TACC, and the Abl Kinase pathway (e.g. Slit, Robo, Orbit), using axonal pathfinding phenotypes in the Drosophila embryonic nervous system as an assay, testing the hypothesis that Msps and TACC function opposite of Orbit and distinguishing between possible genetic models; 2) use biochemical and proteomic analysis to determine if there are direct physical interactions between Msps/TACC, Orbit, and Abl, as well as to expand and define the Msps and TACC interaction networks involved in regulating microtubule dynamics in a Drosophila cell culture line and in neurons; and 3) define the cellular mechanisms of action of Msps and TACC, using highresolution live imaging in Xenopus growth cones. In particular, I will determine if Msps and TACC play a functionally antagonistic role to Orbit, by promoting MT extension towards the growth cone leading edge, or whether they have a different effect on MT dynamics in Xenopus growth cones. Abnormalities in axon guidance have been associated with multiple hereditary neurological disorders and thus this work may shed light on how these defects arise and possibly how to prevent them. Furthermore, mechanisms involved in axon guidance are thought to influence the ability of axons to regenerate after neural injury and so we may be able to use this information to design treatments to allow regeneration in the future. Finally, the proteins studied here are also misregulated in certain cancers. Thus, the research proposed here is of broad biomedical significance.

描述（由申请人提供）：准确的轴突探路是神经系统发育过程中必不可少但高度复杂的过程。轴突形成复杂功能性神经元网络的机制仍然是一个主要难题，并且与了解神经元发育中的异常以及神经再生疗法的异常有关。我的长期目标是定义逻辑，通过该逻辑在轴突探测过程中将指导信息集成在细胞骨架动力学控制水平上。作为解决此问题的起点，我将研究MSP和TACC的作用，MSP和TACC是两个微管相关的蛋白质，最近已被鉴定为ABL酪氨酸激酶效应蛋白轨道的抑制剂，可调节生长锥中的微管动力学，并介导Drosophila Crania drosophila Crisatia Cranis Cranis Cranina Crisation syline Axon抑制。我将使用遗传，生化，蛋白质组学和细胞生物学测定方法来研究MSP，TACC和轨道在生长锥中的功能，以定义相互作用的网络，这些网络在轴突引导过程中协调正和负微管动态。具体而言，我将：1）使用MSP，TACC和ABL激酶途径之间的相互作用的潜在遗传途径（例如Slit，Robo，Orbit），使用Drosophila Embryonic神经系统中的轴突探路表型作为一种测定，以测试MSP和TACC在Orbit的假说和遗传相反的模型，以实现遗传的模型，以实现遗传的模型。 2）使用生化和蛋白质组学分析来确定MSP/TACC，轨道和ABL之间是否存在直接的物理相互作用，以及扩展和定义参与调节果蝇细胞培养线中微管动态的MSP和TACC相互作用网络； 3）使用高分辨率活成像生长锥中的高分辨率实时成像来定义MSP和TACC的作用的细胞机制。特别是，我将确定MSP和TACC是否通过促进MT扩展对生长锥前缘的延伸，或者它们是否对Xenopus生长锥中的MT动力学产生不同的影响来确定对轨道的功能拮抗作用。轴突指导的异常与多种遗传神经系统疾病有关，因此这项工作可能会阐明这些缺陷如何以及如何预防它们。此外，轴突指导中涉及的机制被认为会影响轴突在神经损伤后再生的能力，因此我们可以使用这些信息来设计治疗方法以允许将来再生。最后，这里研究的蛋白质在某些癌症中也被误导。因此，这里提出的研究具有广泛的生物医学意义。