Physiological and Genetic Analysis of Calhm1 function in C. elegans

描述（由申请人提供）：细胞钙离子通道调节在可兴奋细胞信号传导和神经退行性疾病中起关键作用。最近，我们证明了人类Calhm 1基因编码一种新的钙离子通道，并且人类Calhm 1的多态性可能与晚发性阿尔茨海默病有关。虽然这些发现指出了突变型Calhm 1在疾病中的潜在作用，但Calhm 1的生理功能尚不清楚。C.线虫表达一个单一的Calhm 1同源物clhm-1。异源表达的clhm-1产生的电流具有与人Calhm 1相似的特征。与人类Calhm-1一样，蠕虫clhm-1在可兴奋细胞中表达。基于这些数据，我们假设Calhm的生理功能从蠕虫到人类在进化上是保守的。为了确定这些功能，我们将追求两个目标。首先，我们将分析C. elegans clhm-1，以确定Calhm通道功能的保守方面，使用异源表达和原代C. elegans细胞培养物。其次，我们将研究clhm-1在活蠕虫中的功能作用，使用clhm-1敲除菌株和clhm-1过表达策略。我们的研究将提供Calhm功能在体内的第一个详细的研究，并将提供这个新的离子通道家族的重要见解。 公共卫生相关性：细胞钙水平的适当调节对于细胞功能是必不可少的，并且这种调节的紊乱与许多人类神经退行性疾病相关。我们发现一种新的钙离子通道，称为Calhm 1，调节细胞钙水平，人类Calhm 1突变加速了迟发性阿尔茨海默病的病理学。除了这些观察结果，Calhm 1的细胞功能尚不清楚。我们的研究将在模型系统C中研究Calhm 1的功能。并将为这种新蛋白质如何导致人类疾病提供更深入的见解。

DESCRIPTION (provided by applicant): Ion channel regulation of cell calcium plays critical roles in excitable cell signaling and neurodegenerative diseases. Recently, we demonstrated that the human Calhm1 gene encodes for a novel calcium-permeable ion channel and that a human polymorphism in Calhm1 may be linked to late-onset Alzheimer's disease. While these findings point to a potential role for mutant Calhm1 in disease, the physiological function(s) of Calhm1 is unknown. C. elegans expresses a single Calhm1 homolog, clhm-1. Heterologously expressed clhm-1 gives rise to currents with characteristics similar to human Calhm1. Like human Calhm-1, worm clhm-1 is expressed in excitable cells. Based on these data, we hypothesize that the physiological function(s) of Calhm is evolutionarily conserved from worms to humans. To define these functions, we will pursue two aims. First, we will analyze the biophysical properties of C. elegans clhm-1 to determine conserved aspects of Calhm channel function, using both heterologous expression and primary C. elegans cell cultures. Second, we will investigate the functional roles of clhm-1 in live worms, using both clhm-1 knockout strains and clhm-1 overexpression strategies. Our studies will provide the first detailed study of Calhm function in vivo and will offer crucial insights into this new ion channel family. PUBLIC HEALTH RELEVANCE: Proper regulation of cellular calcium levels is essential for cellular function, and derangements in such regulation are associated with numerous human neurodegenerative diseases. We discovered that a new calcium ion channel, called Calhm1, regulates cellular calcium levels and a human Calhm1 mutation accelerates the pathology of Late-onset Alzheimer's disease. Beyond these observations, the cellular function(s) of Calhm1 are unknown. Our proposed studies will investigate Calhm1 function in the model system C. elegans and will provide deeper insights into how this new protein may contribute to human disease.