Modulation of Growth Cone Repellent Responses

生长锥驱避反应的调节

• 批准号: 6994999
• 负责人: STACI D SANFORD
• 金额: $ 2.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-12 至 2009-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994999
• 关键词: arachidonate; biological signal transduction; developmental neurobiology; eicosanoids; embryo /fetus cell /tissue; enzyme activity; growth cones; growth factor; hippocampus; immunoprecipitation; insulinlike growth factor; kinase inhibitor; laboratory rat; linoleate; neurogenesis; neuronal guidance; phospholipase A2; phosphorylation; predoctoral investigator; protein kinase C; thrombin

DESCRIPTION (provided by applicant): A critical step in the establishment of the proper circuitry of the nervous system is the navigation of the growth cones to their correct targets. This process is accomplished through guidance cues and their downstream signaling events. The focus of this proposal is repellent responses of growth cones and their modulation by growth factors. These phenomena are well known, but their mechanisms are poorly understood. The main goal of the proposed research is to elucidate the signaling mechanisms involved in modulation of the repellent response by growth factors. I propose that the eicosanoid-like linoleic acid derivative 13(S)-hydroxyoctadecadienoic acid [13(S)-HODE] plays a key role in this modulation. This research will analyze the mechanism of action of 13(S)-HODE by (1) characterizing the response of growth cones to 13(S)-HODE both alone and upon repellent challenge; (2) investigating whether 13(S)-HODE is an inhibitor of protein kinase C epsilon, whose activity is necessary for growth cone collapse; and (3) identifying the PLA2s responsible for the regulation of free AA and LA. These studies will shed new light on repellent signaling and on the interplay between growth factors and repellents during axon guidance.

描述（由申请人提供）：建立神经系统适当回路的关键步骤是将生长锥导航到其正确的目标。这个过程是通过引导线索及其下游信号事件来完成的。该建议的重点是生长锥的驱避反应及其生长因子的调节。这些现象是众所周知的，但其机制知之甚少。该研究的主要目的是阐明生长因子调节驱避反应的信号传导机制。我认为类二十烷酸亚油酸衍生物13（S）-羟基十八碳二烯酸[13（S）-HODE]在这种调节中起着关键作用。本研究将通过以下方式分析13（S）-HODE的作用机制：（1）表征生长锥对13（S）-HODE单独和驱避剂攻击的响应;（2）调查13（S）-HODE是否是蛋白激酶C β的抑制剂，其活性是生长锥塌陷所必需的;和（3）鉴定负责调节游离AA和LA的PLA 2。这些研究将揭示新的光驱避信号和生长因子和驱避剂之间的相互作用在轴突的指导。