NEUROLOGICAL TARGETS OF ANTIDEPRESSANTS IN C ELEGANS

描述(改编自申请人的摘要)：SSRI抗抑郁药， 包括氟西汀(百忧解)，是最常见的 抑郁症的治疗。氟西汀的体内靶点 对它的抗抑郁作用负责，但它的副作用不是 久负盛名。有系统地在人类或 在哺乳动物中，抑郁症的模型是不可能的。我们使用的是 线虫秀丽线虫鉴定氟西汀的作用机制。 在初步研究中，我们已经确定氟西汀有三种 对线虫有明显的影响。这些影响之一可能是由于 阻断5-羟色胺的再摄取，正如哺乳动物中的一个已知靶点所预期的那样。 另外两种影响似乎与5-羟色胺无关。我们已经隔离了 七个基因的突变使人对其中一种产生抗性 氟西汀(NRF突变体)的非5-羟色胺能作用。我们有分子上的 克隆了其中一个基因，称为NRF-6。NRF-6对定义成员进行编码 属于一个多通道跨膜蛋白家族。我们建议调查 NRF-6通过完成这一初始分子分析并通过确定其 基因表达模式、亚细胞定位和功能部位 赋予氟西汀敏感性。我们建议再克隆两个 我们已经鉴定的氟西汀耐药基因并执行类似的 关于NRF-6的分析。我们建议继续进行诱变筛选以 确定其他调节鼻子收缩和其他氟西汀的基因 回应。最后，我们建议在哺乳动物中识别新的 作为确定NRF-6家族是否 线虫-氟西汀的相互作用可能与人类直接相关。

DESCRIPTION (Adapted from applicant's abstract): The SSRI antidepressants, including fluoxetine (Prozac), are the drugs most commonly prescribed for treatment of depressive disorders. The in vivo targets of fluoxetine that are responsible for its antidepressive effects and its side effects are not well established. Systematically establishing such targets in the human or in mammalian models of depression is not possible. We are using the nematode Caenorhabditis elegans to identify mechanisms of fluoxetine action. In preliminary studies we have established that fluoxetine has three distinct effects in C. elegans. One of these effects is probably due to blocking serotonin reuptake, as expected from one known target in mammals. The other two effects appear not to involve serotonin. We have isolated mutations in seven genes that confer resistance to one of the non-serotonergic effects of fluoxetine (Nrf mutants). We have molecularly cloned one of these genes, called nrf-6. nrf-6 encodes the defining member of a family of multi-pass transmembrane proteins. We propose to investigate nrf-6 by completing this initial molecular analysis and by determining its expression pattern, subcellular localization, and site of function in conferring fluoxetine sensitivity. We propose to clone two additional fluoxetine resistance genes that we have identified and to perform similar analyses as for nrf-6. We propose to continue mutagenesis screens to identify other genes that mediate the nose contraction and other fluoxetine responses. Finally, we propose to identify in mammals members of the new nrf-6 family as a first step toward determining whether the nematode-fluoxetine interaction might have direct relevance to humans.