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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：
8973574
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/8973574
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 Cyclic GMP-Dependent Protein Kinases Cytoskeleton Development Didelphidae Disease Drosophila genus Elements Embryo Emotions Enzymes Equilibrium Event F-Actin Family Family member Figs - dietary Filament GTP-Binding Proteins GTPase-Activating Proteins Goals Grant Guanosine Triphosphate Phosphohydrolases Health 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 Nature Nervous System control Nervous system structure Neuraxis Neurologic Neurons Oxidation-Reduction Oxidoreductase Problem Solving Process Protein Family 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 cellular imaging extracellular fly follow-up genetic regulatory protein graduate student in vivo insight novel plexin polymerization prevent programs receptor relating to nervous system second messenger signal processing

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）：该提案侧重于表征轴突导航和连接的分子机制。正常运作的人类神经系统需要数十亿个神经元的互连。这些连接的不适当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整合的？过去二十年的研究表明，轴突导向和连接的分子机制在简单和复杂动物之间是保守的。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，我们已经采取了一种策略来确定简单模型苍蝇神经系统是如何组装的-我们还可以应用高分辨率分子，遗传，生物化学，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指导轴突的细胞外信号和受体，揭示了轴突如何形成连接的基本机制。然而，我们对细胞内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知之甚少。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，Semaphorins（Semas）。Semas利用丛蛋白，轴突表面上发现的大的跨膜蛋白，作为受体来指导它们的作用。然而，Plexins如何传递信号来塑造连接仍然知之甚少。在过去的几年里，我们在这方面取得了一些进展，为轴突的引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（一个特定的可逆氧化还原机制控制的Mical和SelR酶），直接调节必要的轴突指导和连接的肌动蛋白细胞骨架元素。我们还发现了一组分子相互作用物-- Sema/丛蛋白、G蛋白、激酶、第二信使、衔接子和整合素细胞粘附受体--它们直接调节轴突粘附于其基质的能力。我们的观察使我们假设轴突的引导和连接是由肌动蛋白的可逆氧化还原调节和粘附/去粘附的调节控制的。我们建议通过采用分子、遗传、生物化学、细胞培养和成像方法以及果蝇模型系统来进一步测试这一假设，以跟踪几条初步观察线，这些初步观察确定1）特异性控制Mical介导的肌动蛋白氧化还原调节的活性和定位的新调节酶和2）Sema/丛蛋白/G蛋白介导的去粘附的新分子组分。