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Molecular mechanisms of axon guidance and neural connectivity

轴突引导和神经连接的分子机制

基本信息

批准号：
9180722
负责人：
JONATHAN R TERMAN
金额：
$ 39.75万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180722
关键词：
Actins Adaptor Signaling Protein Adhesions Adhesives Adult Amino Acids Animals Applications Grants Axon Behavior Biochemical Biochemical Genetics Biological Biological Assay Biological Models Brain Diseases Cell Adhesion Cell Culture Techniques Cells Complex Cues Cytoskeleton Development Didelphidae Disease Drosophila genus Elements Embryo Emotions Enzymes Equilibrium Event F-Actin Family Family member Filament G-substrate GTP-Binding Proteins GTPase-Activating Proteins Goals Grant Guanosine Triphosphate Phosphohydrolases Human Image Integral Membrane Protein Integrins Learning Length Lesion Link Location Logic Maintenance Mammals Marsupialia Mediating Mental Health Mental disorders Microfilaments Modeling Molecular Molecular Genetics Monomeric GTP-Binding Proteins Mouse Protein Mus Nature Nervous System control Nervous system structure Neuraxis Neurologic Neurons Oxidation-Reduction Oxides Oxidoreductase Problem Solving Process Protein Family Protein Kinase Protein-Serine-Threonine Kinases Psyche structure Recovery Regulation Research Resolution Scientist Second Messenger Systems Semaphorins Shapes Signal Pathway Signal Transduction Specific qualifier value Spinal Cord Surface System Tertiary Protein Structure Testing Therapeutic Time To specify Trauma Walking Work actin 2 adhesion receptor axon growth axon guidance axon regeneration extracellular fly follow-up genetic regulatory protein graduate student imaging approach in vivo insight novel plexin polymerization prevent programs public health relevance receptor relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on characterizing the molecular mechanisms of axon navigation and connectivity. A normal functioning human nervous system requires the interconnection of billions of neurons. Improper formation or maintenance of these connections leads to neurological abnormalities that result in a number of mental diseases and disorders. How are these connections assembled and integrated? Work over the past twenty years has revealed that the molecular mechanisms of axon guidance and connectivity are well- conserved between simple and complex animals. Simple animals like flies use many of the same guidance signals as mammals. Therefore, as a step towards understanding how complex nervous systems form and properly function, we have pursued a strategy to determine how the simple model fly nervous system is assembled - where we can also apply high-resolution molecular, genetic, biochemical, imaging, and cellular approaches to solving this problem. Indeed, the goal of my research program is to focus on a group of axons within the simple nervous system of the fly embryo and characterize the molecules and mechanisms that guide them to their targets. In particular, elegant studies have now identified a number of the extracellular cues and receptors that guide axons, revealing fundamental mechanisms of how axons form connections. Far less is known, however, of the intracellular signaling pathways and the mechanisms that link these guidance cues and their receptors to the control of axon navigation. As a model, we have been focusing on one of the largest protein families involved in neuronal connectivity, the Semaphorins (Semas). Semas utilize Plexins, large transmembrane proteins found on the axonal surface, as receptors to direct their effects. Yet, how Plexins transduce Sema signals to sculpt connections is still poorly understood. Now, over the past few years, we have had several advances on this front, which have provided new insights into axon guidance and connectivity. We have identified a novel biochemical mechanism (a specific reversible Redox mechanism controlled by Mical and SelR enzymes) that directly regulates the actin cytoskeletal elements necessary for axon guidance and connectivity. We have also uncovered a set of molecular interactors - Sema/Plexins, G proteins, kinases, second messengers, adaptors, and integrin cell adhesion receptors - that directly modulate the ability of an axon to adhere to its substrate. Our observations have led us to hypothesize that axon guidance and connectivity are controlled by both reversible Redox regulation of actin and the modulation of adhesion/de- adhesion. We propose to further test this hypothesis by employing molecular, genetic, biochemical, cell culture, and imaging approaches and the Drosophila model system to follow-up on several lines of preliminary observations that identify 1) new regulatory enzymes that specifically control both the activity and localization of Mical-mediated Redox regulation of actin and 2) new molecular components underlying Sema/Plexin/G- protein-mediated de-adhesion.

描述(由申请人提供)：本提案重点描述轴突导航和连通性的分子机制。正常运作的人类神经系统需要数十亿个神经元的相互连接。这些连接的不正确形成或维持会导致神经异常，从而导致许多精神疾病和障碍。这些连接是如何组装和集成的？过去二十年的研究表明，简单动物和复杂动物之间轴突引导和连接的分子机制是非常保守的。像苍蝇这样的简单动物使用许多与哺乳动物相同的引导信号。因此，作为了解复杂神经系统如何形成和正常运作的一步，我们采取了一种策略来确定简单的飞行神经系统是如何组装的-在那里我们还可以应用高分辨率的分子、遗传、生化、成像和细胞方法来解决这个问题。事实上，我的研究计划的目标是专注于苍蝇胚胎简单神经系统内的一组轴突，并描述引导它们到达目标的分子和机制。特别是，优雅的研究现在已经确定了一些引导轴突的细胞外线索和受体，揭示了轴突如何形成连接的基本机制。然而，对于细胞内的信号通路以及将这些引导信号及其受体与轴突导航控制联系起来的机制，我们知道的要少得多。作为一个模型，我们一直专注于参与神经元连接的最大蛋白质家族之一，信号素(Semaphorins，Semas)。SIMAS利用轴突表面发现的大跨膜蛋白丛状蛋白作为受体来指导它们的作用。然而，丛状蛋白是如何将SEMA信号转导到连接的，目前还知之甚少。现在，在过去的几年里，我们在这方面取得了一些进展，这为轴突指导和连接提供了新的见解。我们已经确定了一种新的生化机制(由Mical和SelR酶控制的特定可逆氧化还原机制)，它直接调节轴突引导和连接所需的肌动蛋白细胞骨架元件。我们还发现了一系列分子相互作用因子--Sema/丛状蛋白、G蛋白、激酶、第二信使、适配器和整合素细胞黏附受体--它们直接调节轴突与其底物的黏附能力。我们的观察使我们假设轴突的引导和连通性既受肌动蛋白可逆氧化还原调节的控制，也受黏附/去黏附调节的控制。我们建议通过使用分子、遗传、生化、细胞培养和成像方法以及果蝇模型系统来进一步验证这一假说，以跟踪几条初步观察结果，这些初步观察确定了1)新的调节酶，它特异性地控制Mical介导的肌动蛋白氧化还原调节的活性和定位，以及2)新的分子成分，这些新的分子成分支撑着Sema/Plexin/G蛋白介导的去黏附。