Function of the Novel Ion Channel narrow abdomen in Daily Rhythms

描述(申请人提供)：紊乱的日常节律与多种脑部疾病有关。这些节律至少由两条相互交织的通路调节，一条是生物钟，另一条是掩蔽通路，负责调节对光的反应。这项提案使用果蝇--黑腹果蝇--解决了这些途径。昼夜节律和掩蔽功能的遗传基础似乎是保守的，这表明在苍蝇身上的发现将被广泛应用。神秘和高度保守的离子通道窄腹(NA)在昼夜节律输出和掩蔽调节中都发挥着关键作用。这些观察结果构成了这项建议的总体目标，即在行为、神经元和分子水平上对NA在掩蔽和昼夜节律方面的功能提供一个综合的观点。该方案的具体目的是：1.定位NA功能的神经底物。NA可能在昼夜节律起搏神经元中起调节掩蔽行为的作用。将进行特定组织的抢救和NA分布的评估，以解决昼夜节律和光感受器神经元的NA功能。还将研究时钟和/或光对NA的调节。2.明确NA突变神经元的电生理表型。发展了一种检测果蝇起搏神经元电特性的方法。将研究这些关键神经元中离子电流的特征，NA对这些电流的影响，以及难以捉摸的NA通道本身的电生理特性，包括生物钟和/或光的调节。3.评估改变的NA信道属性的后果。NA是电压门控阳离子通道家族中一个独特而保守的成员。NA揭示了离子通道的许多特征，包括高度保守的孔选择性和电压传感器序列。具有改变的孔或电压传感器序列的NA通道的功能将通过行为救援进行测试。总之，这些研究将确定NA在与昼夜节律和掩蔽调节相关的不同解剖通路中的电生理功能。考虑到生物钟和NA的保守性，这一提议应该会阐明人类的日常节律及其对疾病的贡献。

DESCRIPTION (provided by applicant): Disturbed daily rhythms have been implicated in a variety of brain disorders. These rhythms are regulated by at least two intertwined pathways, one is the circadian clock and a second is the masking pathway that mediates activity in response to light. This proposal addresses these pathways using the fruit fly, Drosophila melanogaster. The genetic basis of circadian and masking function appears conserved, suggesting that findings in the fly will be widely applicable. A critical role for an enigmatic and highly conserved ion channel narrow abdomen (na) has been identified in both circadian output and masking regulation. These observations underlie the overall goal of this proposal, which is to provide an integrated view of na function in both masking and circadian rhythms at the behavioral, neuronal, and molecular levels. The specific aims of this proposal are: 1. To map the neural substrates of na function. NA may function in circadian pacemaker neurons to regulate masking behavior. Tissue-specific rescue and assessments of NA distribution will be performed to address NA function in circadian and photoreceptor neurons. The regulation of NA by the clock and/or light will also be examined. 2. To define the electrophysiological phenotype of na mutant neurons. A method has been developed to examine the electrical properties of Drosophila pacemaker neurons. Characterization of ionic currents in these key neurons, the effects of na on these currents, as well as the electrophysiological properties of the elusive NA channel itself will be examined, including regulation by the circadian clock and/or light. 3. To assess the consequences of altered NA channel properties. NA is a unique and conserved member of the voltage-gated cation channel family. NA reveals many signatures of ion channels including highly conserved pore selectivity and voltage sensor sequences. The function of NA channels with altered pore or voltage sensor sequences will be tested by behavioral rescue. In total, these studies will define the electrophysiological function of NA within distinct anatomic pathways relevant to circadian and masking regulation. Given the conservation of clocks and NA, this proposal should illuminate human daily rhythms and their contribution to disease.