Regulation of Axonal Transport At Branch Junctions

分支连接处轴突运输的调节

• 批准号: 10383151
• 负责人: Le Ma
• 金额: $ 34.13万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383151
• 关键词: Adult; Afferent Neurons; Axon; Axonal Transport; Behavior; Biological; Cells; Color; Cytoskeleton; Data; Dendrites; Development; Disease; Distal; Dynein ATPase; Embryo; Embryonic Development; Epilepsy; Functional Regeneration; Functional disorder; Genetic; Goals; Growth; Health; Human; Impairment; In Situ; Injury; Kinesin; Knowledge; Light; Link; Location; Lysosomes; MAP1 Microtubule-Associated Protein; Mediating; Membrane; Membrane Proteins; Microtubule-Associated Proteins; Microtubules; Mission; Mitochondria; Modeling; Molecular; Morphogenesis; Motor; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Oranges; Presynaptic Terminals; Proteins; RNA; Recovery of Function; Regulation; Research; Role; Route; Shapes; Signal Transduction; Slice; Specificity; Speed; Spinal Ganglia; Synapses; Testing; Time; United States National Institutes of Health; anterograde transport; base; cell age; cell type; experimental study; insight; interest; molecular imaging; nerve injury; nervous system disorder; novel; optogenetics; preference; recruit; response; synaptic function; tool; trafficking

Axonal transport is essential to development and function of the nervous system. Axonal transport relies on motor proteins (kinesins and dynein) to move protein, membrane and RNA cargos along microtubules. It is especially important to long and often highly branched axons that requires building blocks made in the cell body or signals received at axonal terminals to be transported for long distance. Recently studies have identified many regulatory mechanisms, including the interactions between motor proteins with lattice-bound microtubule associated proteins (MAPs), in different axonal regions. However, how axonal transport is regulated to steer cargos into and out of branches is not well understood. This is an outstanding problem as axonal branches are present throughout the nervous system. They not only define neuronal shape, but also control synaptic connectivity and specificity, influence structural plasticity, and promote functional regeneration after injury. The proposed study will tackle this under-studied problem by building on our long-term interest in branch morphogenesis and cytoskeleton regulation as well as a recent discovery of a MAP in branch development and transport regulation. Our preliminary data showed that transport at branch junctions is highly selective as cargos are preferentially transported into growing branches. In addition, we also found that MAP7, a MAP that is localized to branch junctions and interacts with the plus end motor kinesin-1, influences transport behavior and branch growth. We thus hypothesize that axonal transport at branch junctions is controlled by a selective routing mechanism that is mediated by specific motor-MAP interactions. To test this hypothesis, we will: 1) establish a functional link between selective transport and branch growth; 2) dissect the mechanism mediated by MAP7; and 3) establish selective routing as a common feature in axonal transport. By focusing on an important region of the axon that has not been studied in the past, these studies will not only fill in a gap in our understanding of axonal transport, but also provide new insights into synaptic development and function. Given the importance of axonal transport in many neurological and neurodegenerative disorders, and the association of MAP7 and kinesin-1 with epilepsy and ALS, our proposed studies of a basic neuronal cell biological problem will provide new knowledge to uncover disease mechanisms, and thus are highly relevant to the NIH mission to understand and enhance human health.

轴突运输对于神经系统的发育和功能是必不可少的。轴突运输 依靠马达蛋白(动蛋白和动力蛋白)沿微管移动蛋白质、膜和RNA货物。 对于需要在细胞中构建积木的长的、通常是高分支的轴突来说，这一点尤其重要。 在轴突终末接收到的身体或信号被长距离传输。最近的研究表明 确定了许多调节机制，包括马达蛋白与晶格结合之间的相互作用 微管相关蛋白(MAP)，在不同的轴突区域。然而，轴突运输是如何 对引导货物进出分支机构的监管还没有得到很好的理解。这是一个突出的问题，因为 轴突分支遍布神经系统。它们不仅定义了神经元的形状，而且还 控制突触连通性和特异性，影响结构可塑性，促进功能再生 受伤后。建议的研究将以我们长远的利益为基础，解决这个研究不足的问题。 分支的形态发生和细胞骨架调控以及最近在分支中发现的图谱 发展和运输监管。我们的初步数据显示，分支路口的交通高度集中 有选择性的，因为货物优先运输到正在生长的树枝上。此外，我们还发现MAP7， 定位于分支连接并与正端马达Kinesin-1相互作用的MAP影响运输 行为和枝条生长。因此，我们假设在分支连接处的轴突运输是由一个 由特定的运动映射相互作用所调节的选择性路由机制。为了检验这一假设，我们 将：1)建立选择性运输与枝条生长之间的功能联系；2)剖析选择性运输与枝条生长的机制 由MAP7介导；以及3)建立选择性路径作为轴突运输的共同特征。通过聚焦 在轴突的一个过去没有研究过的重要区域，这些研究不仅填补了一个空白 在我们了解轴突运输的同时，也为突触的发育和功能提供了新的见解。 鉴于轴突运输在许多神经和神经退行性疾病中的重要性，以及 MAP7和Kinesin-1与癫痫和肌萎缩侧索硬化症的关系--我们提出的基础神经细胞研究 生物学问题将为揭示疾病机制提供新的知识，因此与 美国国立卫生研究院的使命是了解和提高人类健康。