A Potential Role for NaV1.1 in Taste Signal Transmission

项目摘要 电压门控钠通道NaV1.1已成为味觉信号传递的可能候选者 根据临床观察，患有Dravet综合征（DS）的儿科患者， 由NaV1.1单倍不足引起的通道病，表现出对甜味的冷漠或厌恶 食物-在儿童中非常不寻常的发现。RNA-seq转录组学数据显示，NaV1.1表达于 神经节细胞的亚群被认为传递特殊的味觉品质，包括甜味。我的初步 行为和电生理研究也表明，NaV1.1可能介导甜味信号 在急性（即药理学阻断）小鼠模型以及NaV1.1的遗传模型中， 单倍不足在这项提议中，三种不同的小鼠模型--一种急性和两种遗传--将被用于研究。 评估由于Nav1.1功能障碍引起的外周味觉缺陷（目标1）和行为影响（目标2）。这 这项研究是创新性的，因为我们的初步数据表明：1）单一类型的钠通道可能 不同地影响特定味觉品质的传递，以及2）味觉功能可以用作 NaV1.1功能替代测量。后者将是特别有用的评估表型严重程度 在Dravet患者中，迄今为止还没有稳健的生物标志物用于评估。

Project Summary The voltage-gated sodium channel NaV1.1 has emerged as a possible candidate in gustatory signal transmission following the clinical observation that pediatric patients with Dravet syndrome (DS), an epileptic channelopathy resulting from NaV1.1 haploinsufficiency, demonstrate an indifference or aversion to sweet foods – a highly unusual finding in children. RNA-seq transcriptomic data shows that NaV1.1 is expressed in subsets of ganglion cells thought to transmit particular taste qualities, including sweet. My preliminary behavioral and electrophysiological studies also suggest that NaV1.1 may mediate sweet taste signal transmission, both in an acute, i.e. pharmacological block, mouse model as well as in a genetic model of NaV1.1 haploinsufficiency. In this proposal, three different mouse models – one acute and two genetic – will be assessed on peripheral gustatory deficits (Aim 1) and behavioral effects (Aim 2) due to Nav1.1 dysfunction. This study is innovative because our preliminary data suggest that 1) a single type of sodium channel may differentially impact transmission of particular taste qualities, and 2) gustatory function may serve as a surrogate measure for NaV1.1 function. The latter would be particularly useful for assessing phenotype severity in Dravet patients, which as of yet does not have a robust biomarker to use in assessment.