Modulation of Growth Cone Repellent Responses

描述(由申请人提供)：建立适当的神经系统回路的关键一步是将生长锥体导航到它们正确的目标。这一过程是通过指导提示及其下游信令事件完成的。这项提议的重点是生长锥体的排斥反应以及生长因子对它们的调节。这些现象是众所周知的，但其机制却鲜为人知。这项研究的主要目的是阐明生长因子调节排斥反应的信号机制。我认为二十烷类亚油酸衍生物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。本研究将从以下几个方面分析13(S)-HODE的作用机制：(1)表征生长锥对13(S)-HODE单独和排斥攻击的反应；(2)研究13(S)-HODE是否是蛋白激酶C epsilon的抑制剂，其活性是生长锥崩溃所必需的；(3)鉴定负责调节游离AA和LA的PLA2。这些研究将对排斥信号以及生长因子和排斥因子在轴突引导过程中的相互作用提供新的线索。

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.