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，儿童癫痫患者中的德拉韦氏综合征(DS) NAV1.1单倍体功能不全引起的经络病，表现出对甜食的漠视或厌恶 食物--这在儿童中是一个非常不寻常的发现。RNA-seq转录数据显示，Nav1.1在 神经节细胞的亚群，被认为传递特殊的味道，包括甜味。我的初选 行为学和电生理学研究也表明，Nav1.1可能介导甜味信号 急性传播，即药物阻断，小鼠模型以及Nav1.1的遗传模型 单倍体功能不全。在这项提案中，三种不同的小鼠模型--一种急性模型和两种遗传模型--将 评估由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 这项研究具有创新性，因为我们的初步数据表明：1)单一类型的钠通道可能 不同地影响特定口味品质的传递，以及2)味觉功能可能起到 Nav1.1函数的代理度量。后者对于评估表型严重性特别有用 在DraveT患者中，到目前为止还没有一个强大的生物标记物用于评估。

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.