Microtubule Dynamics and Axon Growth

微管动力学和轴突生长

• 批准号: 9198152
• 负责人: PETER W. BAAS
• 金额: $ 3.05万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198152
• 关键词: Adverse effects; Applications Grants; Automobile Driving; Axon; Back; Biological; Cancer Patient; Cells; Clinical; Data; Degenerative Disorder; Dendrites; Development; Disease; Distal; Dynein ATPase; Elements; Environment; Funding; Goals; Health; Imaging Techniques; Injury; Kinesin; Knowledge; Left; Length; Medical; Microtubules; Minus End of the Microtubule; Mitosis; Mitotic; Mitotic Activity; Modeling; Molecular Motors; Motor; Movement; Natural regeneration; Nerve; Neurites; Neurodegenerative Disorders; Neurons; Organelles; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Rest; Role; Site-Directed Mutagenesis; Staging; Testing; Time; Tissues; Tubulin; Work; axon growth; axon regeneration; base; cancer therapy; clinical risk; injured; innovation; live cell imaging; neuron development; novel; novel strategies; protein transport; research study; retrograde transport; trafficking

DESCRIPTION (provided by applicant): Microtubules are essential architectural elements within axons and dendrites that also act as railways for organelle transport. Axonal microtubules are nearly uniformly oriented with their plus ends distal to the cell body, while microtubules in vertebrate dendrites are non-uniformly oriented. These patterns are established by motor proteins that transport microtubules with different orientations into each type of process. Cytoplasmic dynein transports many of the microtubules with plus-ends leading, with the remainder of the work left to a class of kinesins best known for their roles in mitosis. The bona fide transport of microtubules occurs only when the microtubules are relatively short, but the forces imposed by these motors act on microtubules of all lengths. The forces imposed on long microtubules are important for determining whether the axon (and presumably dendrites) grows or retracts as well as for steering it toward its target tissues. The overall goal of this grant proposal is to understand how the relevant motors are regulated so that they can perform these important functions. Such knowledge will be instrumental for developing strategies for augmenting regeneration of injured nerves and for correcting flaws in microtubule orientation that can cause "traffic jams" in degenerating axons. The first specific aim seeks to elucidate the polarity orientation of the short mobile microtubules in the axon in order to test the hypothesis that mal-oriented microtubules are transported back to the cell body as a means of preserving the microtubule polarity pattern of the axon. Additional experiments are aimed at identifying the motors that transport microtubules of each orientation in their respective directions. The second aim seeks to test the hypothesis that the mitotic motors act at the level of the cell body to impose a limit on the transport of plus-end-distal microtubules into the axon while at the same time driving minus-end-distal microtubules into dendrites. The third aim seeks to investigate a potential role for post-translational modifications of tubulin in regulating the interaction of the relevant motors with microtubules in different compartments of the neuron. The proposed studies will utilize novel live-cell imaging techniques on cultured neurons, as well as innovative cell biological approaches for manipulating the relevant motor proteins.

描述（由申请人提供）：微管是轴突和树突中的必不可少的建筑元素，它们也充当了Organelle运输的铁路。轴突微管几乎均匀地定向，其上的末端离细胞体远端，而脊椎动物树突中的微管则是不均匀的。这些模式是由运动蛋白建立的，该运动蛋白将具有不同方向的微管传输到每种过程中。细胞质动力蛋白将许多微管运输，其余的作品剩下的作品留给了一类驱动蛋白，以其在有丝分裂中的作用而闻名。微管的真正运输仅在微管相对较短时才发生，但是这些电动机施加的力作用于所有长度的微管上。在长微管上施加的力对于确定轴突（和可能是树突）是否会生长或缩回以及将其转向其靶组织。该赠款提案的总体目标是了解如何对相关电机进行调节，以便它们可以执行这些重要功能。这种知识将有助于制定策略来增强受伤神经的再生并纠正微管取向的缺陷，从而导致退化轴突中的“交通拥堵”。第一个特定的目的旨在阐明轴突中短移动微管的极性取向，以检验以下假设，即将其面向MAL面向的微管转移到细胞体中，以保留轴突的微管极性模式。其他实验旨在识别电动机在各自的方向上运输每个方向的微管。第二个目的旨在检验假设，即有丝分裂电动机在细胞体的水平上作用，以限制将正端依从微管转运到轴突中，同时驱动负端端微管进入树突。第三个目标旨在研究小管蛋白在调节相互作用中翻译后修饰的潜在作用。 与神经元不同隔室中微管的相关电机。拟议的研究将利用有关培养神经元的新型活细胞成像技术，以及来操纵相关运动蛋白的创新细胞生物学方法。