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.
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