Myosin-Va and axonal protein synthesis

肌球蛋白-Va 和轴突蛋白合成

基本信息

批准号：
7343624
负责人：
JOHN A MERCER
金额：
$ 3.97万
依托单位：
MC LAUGHLIN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7343624
关键词：
Actins Alleles Antibodies Axon Biochemistry Biological Phenomena Bypass Cell Line Cells Cellular biology Collaborations Communication Cytoplasm Dependence Disease Family Foundations Gene Expression Grant Growth Hela Cells Injury Knock-in Mouse Laboratories Lipids MYO5A gene Maintenance Melanosomes Messenger RNA Microtubules Molecular Genetics Motor Activity Mus Myosin ATPase Myosin Type V Natural regeneration Nervous System Physiology Neuroglia Neurons Organelles Peripheral Physiology Problem Solving Process Protein Biosynthesis Proteins Publishing Research Ribosomal Proteins Ribosomes Schwann Cells Structure System Testing Transcript Transgenic Mice Transgenic Organisms Tubular formation United States National Institutes of Health Uruguay base foot member mutant neuronal cell body parent grant programs protein degradation therapy development

项目摘要

DESCRIPTION (provided by applicant): Evidence for axonal protein synthesis was first published more than two decades ago. The vertebrate axonal translational machinery is organized as periaxoplasmic ribosomal plaques (PARPs), first described in 1996. The demonstration that the axonal territory has its own protein synthesis machinery was initially controversial, but now is generally accepted. Axonal protein synthesis expands the scope of our understanding of both normal and pathological physiology of central and peripheral axons. Our analyses of axonal functions such as growth, guidance, regeneration, and plasticity must now incorporate the possibility of dependence on a local gene expression system. While axonal protein synthesis solves problems with protein turnover, it creates new questions about stability and origins of the proteins and messenger RNAs found in periaxoplasmic ribosomal plaques. In this FIRCA application, we hypothesize that the axonal ribosomes, the myosin- Va associated with them, and/or the messenger RNAs associated with them are supplied to the axon by Schwann cells. To test the first two aspects of this hypothesis, we will determine the origin (neuronal or glial) of myosin-Va and the transcript encoding it using transgenic mice in which a tagged myosin-Va is expressed specifically in glial cells. Second, to determine the origin of axonal ribosomes, we will use transgenic mice in which a tagged ribosomal protein is expressed specifically in glial cells or neurons. This research will be done primarily in Uruguay at the Instituto de Investigaciones Biolsgicas Clemente Estable in collaboration with Dr. Josi Roberto Sotelo as an extension of NIH grant R01GM066901.An understanding of the communication between the axons of neurons and the Schwann cells that ensheath and myelinate them is essential in the development of therapies to regenerate nervous system function after injury and disease. If the underlying hypothesis of this application is correct, it may be possible to directly supplement or program axons with messenger RNAs and proteins, bypassing the neuronal cell body, which can be up to three feet away.

描述（由申请人提供）：轴突蛋白质合成的证据首次发表于二十多年前。脊椎动物的轴突翻译机制被组织为轴突周围核糖体斑块 (PARP)，于 1996 年首次被描述。轴突区域具有自己的蛋白质合成机制的论证最初存在争议，但现在已被普遍接受。轴突蛋白质合成扩大了我们对中枢和外周轴突正常和病理生理学的理解范围。我们对轴突功能（例如生长、引导、再生和可塑性）的分析现在必须纳入对局部基因表达系统依赖的可能性。虽然轴突蛋白质合成解决了蛋白质周转问题，但它也产生了关于轴浆周核糖体斑块中蛋白质和信使 RNA 的稳定性和起源的新问题。在此 FIRCA 应用中，我们假设轴突核糖体、与其相关的肌球蛋白-Va 和/或与其相关的信使 RNA 由雪旺细胞提供给轴突。为了检验该假设的前两个方面，我们将使用转基因小鼠确定肌球蛋白-Va 的起源（神经元或神经胶质细胞）和编码它的转录物，其中标记的肌球蛋白-Va 在神经胶质细胞中特异性表达。其次，为了确定轴突核糖体的起源，我们将使用转基因小鼠，其中标记的核糖体蛋白在神经胶质细胞或神经元中特异性表达。这项研究将主要在乌拉圭 Instituto de Investigaciones Biolsgicas Clemente Estable 与 Josi Roberto Sotelo 博士合作完成，作为 NIH 拨款 R01GM066901 的延伸。了解神经元轴突与包覆和髓鞘形成的雪旺细胞之间的通信它们对于开发损伤和疾病后恢复神经系统功能的疗法至关重要。如果该应用的基本假设是正确的，那么就有可能直接用信使 RNA 和蛋白质补充或编程轴突，绕过最远三英尺远的神经元细胞体。