The role of ppk ion channels in sensory detection

描述(申请人提供)：离子通道将细胞外环境的变化转化为神经活动。降解素/上皮钠离子通道家族参与了许多生物体的基本过程，从哺乳动物肾脏的盐交换、线虫的机械转导到蜗牛的多肽感觉。在果蝇中，这种被称为扒窃基因(PPK)的基因家族有29个成员。在果蝇中可用的分子、遗传、功能和行为分析为剖析该基因家族中未表征成员的功能提供了机会。在初步研究中，已发现PPK基因家族中的两个成员仅在成年果蝇的感觉神经元中表达。本申请的目的是阐明它们的功能。拟议的实验将检查含有PPK的细胞检测到的配体，与特定PPK基因丢失相关的细胞和行为表型，以及被设计为错误表达PPK离子通道的细胞的反应谱。拟议的实验将检验PPK离子通道直接检测细胞外感觉线索的假设。这些研究将阐明PPK离子通道的生物学作用，并确定激活它们的配体。由于该离子通道家族的成员与多种人类疾病有关，因此对PPK功能的研究直接关系到人类的健康。公共卫生相关性：这项研究与公共健康相关，因为它检查了与人类疾病相关的离子通道的功能。这些通道的原发功能障碍是几种重要人类疾病的病理生理学基础，如盐敏感型高血压和假性低醛固酮增多症I型，这些通道的缺陷与囊性纤维化和癫痫有关。对连接这些离子通道的配体的基本了解可能最终会提供对人类疾病基因的洞察，并对公共健康产生直接影响。

DESCRIPTION (provided by applicant): Ion channels transduce changes in the extracellular environment into neural activity. The Degenerin/Epithelial sodium channel family of ion channels participates in fundamental processes in many organisms, from salt exchange in mammalian kidneys, mechanotransduction in C. elegans, and peptide sensing in snails. In Drosophila, there are 29 members of this gene family called pickpocket genes (ppk). The molecular, genetic, functional and behavioral assays available in Drosophila provide the opportunity to dissect the function of uncharacterized members of this gene family. In preliminary studies, two members of the ppk gene family have been identified that are exclusively expressed in sensory neurons in the adult Drosophila. The aim of this application is to elucidate their function. The experiments proposed will examine the ligands that are detected by ppk-containing cells, the cellular and behavioral phenotypes associated with loss of specific ppk genes, and response profiles of cells engineered to mis-express ppk ion channels. The proposed experiments will examine the hypothesis that ppk ion channels directly detect extracellular sensory cues. These studies will elucidate the biological role of ppk ion channels and determine the ligands that activate them. Because members of this ion channel family are associated with diverse human diseases, studies of ppk function are directly relevant to human health. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it examines the function of ion channels that are associated with human disease. Primary malfunctions in these channels underlie the pathophysiology of several important human diseases such as salt-sensitive hypertension and pseudohypoaldosteronism type I, and defects in these channels have been associated with cystic fibrosis and epilepsy. A basic understanding of the ligands that gate these ion channels may ultimately provide insight into human disease genes, with a direct impact on public health.