UNC-73/Trio Signaling In Axon Guidance and Neurotransmission
轴突引导和神经传递中的 UNC-73/Trio 信号传导
基本信息
- 批准号:7457522
- 负责人:
- 金额:$ 21.6万
- 依托单位:
- 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:2008-04-01 至 2012-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffectAldicarbAnimal ModelAnnona muricata coroninAxonBehaviorBehavior DisordersBehavioralBiological AssayCaenorhabditis elegansCellsChromosome PairingCognition DisordersComplement component C1sComplexCuesCytoskeletonDH DomainDataDefectDevelopmentDrosophila genusEventFamilyGTP Phosphohydrolase ActivatorsGenesGeneticGenetic EpistasisGenetic ScreeningGoalsGrowth ConesGuanosine Triphosphate PhosphohydrolasesHeterotrimeric GTP-Binding ProteinsHumanIndividualKnowledgeLinkLocomotionMammalsMapsMembraneMembrane Protein TrafficMolecularMovementMutationNervous system structureNeuromodulatorNeuronsNeuropeptidesPathway interactionsPhenotypePhysiologicalPlayProcessProductionProtein BindingProtein IsoformsProteinsPublic HealthRegulationRoleScreening procedureSignal PathwaySignal TransductionSignaling MoleculeSiteSpinal cord injurySynapsesTestingVesicleWorkYeastsaxon guidancebasecholinergic synapsecoronin proteindesigngenetic analysisin vivoinsightmature animalmutantnervous system developmentnervous system disorderneurotransmissionpolymerizationpromoterreceptorreceptor functionresearch studyrhorho GTP-Binding Proteinsscaffoldsynaptic functiontherapy developmenttraffickingyeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): The general goal of this proposal is to develop our knowledge of the basic mechanisms of axon extension and neurotransmission as they relate to signaling through Rho-family GTPases. Rho GTPase pathway defects in Drosophila and C. elegans affect both axon pathfinding during the development of the nervous system and neurotransmission in adult animals. These defects dramatically alter locomotory behavior in C. elegans, and in humans Rho pathway defects can result in severe cognitive disorders. Therefore, a better understanding of Rho-family GTPase signaling will further our knowledge of the molecular mechanisms underlying behavior and will facilitate the development of treatments for those with spinal cord injuries or behavioral disorders. The present study is designed to use the model organism C. elegans to examine signaling involving the Rho family GTPase activator UNC-73/Trio in both axon guidance and neurotransmission. My previous work established that the unc-73 locus is complex and encodes two distinct RhoGEF domains in several different protein isoforms. The UNC-73 B isoform contains the Rac GTPase specific RhoGEF-1 domain and functions in axon guidance. The UNC-73 C1, C2 and E isoforms function in neurotransmission and contain the Rho specific RhoGEF-2 domain. The specific aims of this proposal are to identify and characterize molecules that function with UNC-73 in Rho GTPase pathways and to better define how the Rho GTPase pathways function in axon guidance and neurotransmission. Preliminary experiments identified two important UNC-73 B interacting proteins, POD-1 and GEI-18, that are each involved in the regulation of actin polymerization and membrane trafficking events and therefore provide insight into the mechanisms of Rac pathway functions in axon guidance. The first specific aim is to characterize the POD-1 and GEI- 18 proteins and their interaction with UNC-73 using protein/protein binding assays, in vivo co- localization and genetic analysis. The second and third specific aims focus on the role of the UNC-73 isoforms in the process of neurotransmission. Intriguing preliminary data places the UNC-73 RhoGEF- 2 isoforms in a genetic pathway of synapse regulation upstream of the G1s heterotrimeric G protein. My hypothesis is that UNC-73 RhoGEF-2 isoforms function in a neuromodulator signaling pathway to influence neurotransmission. This will be tested by analyzing: 1) specific unc-73 mutants in aldicarb sensitivity assays, 2) neuromodulator production in specific neurons in these mutants and 3) the phenotypes of unc-73 double mutants containing mutations in genes involved in neuropeptide signaling. In addition a genetic screen for suppressors of an unc-73 neurotransmission defective mutant will be performed to identify additional components of the UNC-73 signaling pathway. PUBLIC HEALTH RELEVANCE The goal of this proposal is to develop our knowledge of the mechanisms by which neurons, the cells of the nervous system, are assembled into a complex circuitry in the process of axon guidance and how these cells communicate with each other in the process of neurotransmission. A detailed understanding of these essential processes will eventually allow us to devise better treatments for those with spinal cord injuries or neurological disorders that affect behavior.
描述(由申请人提供):该提案的总体目标是加深我们对轴突延伸和神经传递基本机制的了解,因为它们与通过 Rho 家族 GTP 酶进行的信号传导有关。果蝇和线虫中的 Rho GTPase 通路缺陷会影响成年动物神经系统发育过程中的轴突寻路和神经传递。这些缺陷极大地改变了线虫的运动行为,而在人类中,Rho 通路缺陷可能导致严重的认知障碍。因此,更好地了解 Rho 家族 GTPase 信号传导将进一步加深我们对行为背后分子机制的了解,并将有助于开发针对脊髓损伤或行为障碍患者的治疗方法。本研究旨在使用模型生物线虫来检查涉及 Rho 家族 GTP 酶激活剂 UNC-73/Trio 在轴突引导和神经传递中的信号传导。我之前的工作证实 unc-73 基因座很复杂,并且在几种不同的蛋白质亚型中编码两个不同的 RhoGEF 结构域。 UNC-73 B 同工型包含 Rac GTPase 特异性 RhoGEF-1 结构域和轴突引导功能。 UNC-73 C1、C2 和 E 同工型在神经传递中发挥作用,并包含 Rho 特异性 RhoGEF-2 结构域。该提案的具体目的是识别和表征 Rho GTP 酶途径中与 UNC-73 一起发挥作用的分子,并更好地定义 Rho GTP 酶途径如何在轴突引导和神经传递中发挥作用。初步实验确定了两种重要的 UNC-73 B 相互作用蛋白 POD-1 和 GEI-18,它们各自参与肌动蛋白聚合和膜运输事件的调节,因此提供了对轴突引导中 Rac 通路功能机制的深入了解。第一个具体目标是使用蛋白质/蛋白质结合测定、体内共定位和遗传分析来表征 POD-1 和 GEI-18 蛋白质及其与 UNC-73 的相互作用。第二个和第三个具体目标集中于 UNC-73 同工型在神经传递过程中的作用。有趣的初步数据将 UNC-73 RhoGEF-2 亚型置于 G1s 异三聚体 G 蛋白上游突触调节的遗传途径中。我的假设是 UNC-73 RhoGEF-2 同工型在神经调节信号通路中发挥作用,从而影响神经传递。这将通过分析进行测试:1) 涕灭威敏感性测定中的特定 unc-73 突变体,2) 这些突变体中特定神经元中神经调节剂的产生,以及 3) 包含参与神经肽信号转导的基因突变的 unc-73 双突变体的表型。此外,还将对 unc-73 神经传递缺陷突变体的抑制子进行遗传筛选,以鉴定 UNC-73 信号通路的其他成分。公共健康相关性 该提案的目标是加深我们对神经元(神经系统细胞)在轴突引导过程中组装成复杂电路的机制的了解,以及这些细胞在此过程中如何相互通信的神经传递。对这些基本过程的详细了解最终将使我们能够为那些患有脊髓损伤或影响行为的神经系统疾病的人设计出更好的治疗方法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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