Modulation of Growth Cone Repellent Responses

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正确的目标。这一过程是通过引导信号及其下游信号事件完成的。本研究的重点是生长锥的驱避反应及其受生长因子的调节。这些现象是众所周知的，但它们的机制却知之甚少。本研究的主要目的是阐明生长因子调节驱避反应的信号机制。我认为类二十烷酸亚油酸衍生物13(S)-羟基十八烯二烯酸[13(S)-HODE]在这种调制中起关键作用。本研究将分析13(S)-HODE的作用机制，通过(1)描述生长球果对13(S)-HODE单独和驱避攻击的反应；(2)研究13(S)-HODE是否是蛋白激酶C epsilon的抑制剂，其活性是生长锥塌陷所必需的；(3)确定负责免费AA和LA监管的plas。这些研究将为驱避信号以及生长因子和驱避剂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.