Function of the Novel Ion Channel narrow abdomen in Daily Rhythms

描述（由申请人提供）：日常节律紊乱与多种脑部疾病有关。这些节律至少受到两条相互交织的途径的调节，一是生物钟，二是介导响应光的活动的掩蔽途径。该提案利用果蝇（Drosophila melanogaster）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，这表明果蝇中的发现将广泛适用。神秘且高度保守的窄腹离子通道 (na) 在昼夜节律输出和掩蔽调节中发挥着关键作用。这些观察结果构成了该提案的总体目标，即在行为、神经元和分子水平上提供掩蔽和昼夜节律中 na 功能的综合视图。该提案的具体目标是： 1. 绘制 na 功能的神经底物图。 NA 可能在昼夜节律起搏神经元中发挥作用，调节掩蔽行为。将进行组织特异性救援和 NA 分布评估，以解决昼夜节律和感光神经元中的 NA 功能。还将检查时钟和/或光对 NA 的调节。 2. 定义na突变神经元的电生理表型。已经开发出一种方法来检查果蝇起搏器神经元的电特性。将检查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 NA 通道特性改变的后果。 NA 是电压门控阳离子通道家族中独特且保守的成员。 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。总的来说，这些研究将定义 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。考虑到时钟和 NA 的保护，该提案应该阐明人类的日常节律及其对疾病的影响。

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.