Investigation of asymmetric signaling complexes in axon guidance.

轴突引导中不对称信号复合物的研究。

• 批准号: 7826649
• 负责人: CHRISTOPHER C QUINN
• 金额: $ 7.39万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826649
• 关键词: Autistic Disorder; Axon; Binding; Binding Sites; Complex; Consensus; Cues; Cytoplasmic Protein; Data; Development; Disease; Down Syndrome; Event; Failure; Genes; Goals; Grant; Growth; Growth Cones; Guanosine Triphosphate Phosphohydrolases; Human; Investigation; Learning; Light; Mediating; Mental Retardation; Mutation; Natural regeneration; Nervous system structure; Neurons; Pathway interactions; Phenocopy; Process; Proline; Proteins; Research; Role; Signal Pathway; Signal Transduction; Structure; Tertiary Protein Structure; Work; axon growth; axon guidance; extracellular; intersectin 1; member; nerve injury; nervous system disorder; neural circuit; prevent; protein complex; protein function; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Growth cone guidance is critical for the establishment of appropriate connectivity among neurons and failures in this process can result in psychiatric and neurological disease. Several extracellular guidance cues and their receptors have been implicated in growth cone guidance. However, the intracellular mechanisms that mediate the response to these cues are not well understood. Activation of the Rac GTPase is thought to be a key step in the transduction of guidance signals. However, our understanding of the events downstream of Rac activation is limited. Recent work has implicated MIG-10/lamellipodin as an effector for Rac during the guidance response. Activation of Rac triggers binding to MIG-10/lamellipodin and asymmetric localization of MIG-10/lamellipodin in response to a guidance cue. The immediate goal of this application is to identify additional members of the MIG-10/lamellipodin signaling pathway. Identification of these proteins will provide preliminary data for a larger research application that will seek to determine how asymmetric localization of signaling complexes is established and how this asymmetric localization results in directional responses to guidance cues. PUBLIC HEALTH RELEVANCE: Mutations in genes that encode components of the Rac signaling pathway can cause mental retardation in humans. Furthermore, Rac inactivation has been implicated in the inhibitory signaling pathways that prevent neuronal regeneration. Therefore, an understanding of how Rac and MIG-10/lamellipodin function to control axon growth and guidance will be useful in efforts to treat mental retardation and neural injury.

描述（由申请人提供）：生长锥指南对于在此过程中建立适当的连通性和失败可能导致精神病和神经系统疾病至关重要。 细胞外引导提示及其受体已与生长锥指导有关。 但是，介导对这些线索的反应的细胞内机制尚不清楚。 RAC GTPase的激活被认为是指导信号转导的关键步骤。 但是，我们对RAC激活下游事件的理解是有限的。 最近的工作已牵涉MIG-10/lamellipodin作为指导响应期间RAC的效应子。 RAC触发器与Mig-10/lamellipodin结合的激活以及Mig-10/lamellipodin的不对称定位，响应于引导提示。 该应用程序的直接目标是确定MIG-10/Lamellipodin信号通路的其他成员。 这些蛋白质的识别将为较大的研究应用提供初步数据，该数据将寻求确定信号复合物的不对称定位以及这种不对称定位如何导致对指导提示的方向响应。 公共卫生相关性：编码RAC信号通路组成部分的基因突变会导致人类的智力降低。 此外，RAC失活与预防神经元再生的抑制信号传导途径有关。 因此，了解RAC和MIG-10/Lamellipodin如何控制轴突生长和指导将在治疗智力低下和神经损伤方面有用。