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: 7635016
• 负责人: CHRISTOPHER C QUINN
• 金额: $ 7.8万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-06 至 2010-01-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635016
• 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）：生长锥引导对于神经元之间建立适当的连接至关重要，此过程中的失败可能导致精神和神经系统疾病。 一些细胞外引导信号及其受体与生长锥引导有关。 然而，介导对这些线索的反应的细胞内机制尚不清楚。 Rac GTPase 的激活被认为是引导信号转导的关键步骤。 然而，我们对 Rac 激活下游事件的了解是有限的。 最近的研究表明 MIG-10/lamellipodin 在指导响应期间是 Rac 的效应子。 Rac 的激活会触发与 MIG-10/lamellipodin 的结合，并根据引导提示触发 MIG-10/lamellipodin 的不对称定位。 该应用的直接目标是确定 MIG-10/lamellipodin 信号通路的其他成员。 这些蛋白质的鉴定将为更大的研究应用提供初步数据，该应用将寻求确定信号复合物的不对称定位是如何建立的以及这种不对称定位如何导致对引导线索的定向反应。 公共健康相关性：编码 Rac 信号通路成分的基因突变可能导致人类智力低下。 此外，Rac 失活与阻止神经元再生的抑制性信号通路有关。 因此，了解 Rac 和 MIG-10/lamellipodin 如何发挥控制轴突生长和引导的作用将有助于治疗精神发育迟滞和神经损伤。