Investigation of Calcium Signaling in Caenorhabditis elegans

总结/摘要 钙是一种多功能的信号分子，是许多细胞过程的关键介质，包括肌肉 收缩、转录、细胞分裂和突触囊泡释放。特别是，钙也可以触发细胞 死亡和细胞坏死。因此，钙信号传导的失调可以以不同的方式影响细胞， 不同程度地因此，需要严格控制钙水平。事实上，缺钙 信号传导与许多神经变性疾病、肌营养不良和心脏病有关。 为了了解钙信号的调节，我们正在利用秀丽隐杆线虫模型系统 以确定钙处理调节中涉及的关键组件。从我们的无偏见 在遗传学研究中，我们发现了一种保守蛋白SEL-12在内质网钙离子通道中的新作用， 这对线粒体的形态组织和功能至关重要。SEL-12是C. elegans 早老素同系物。早老素突变是早发性家族性阿尔茨海默病最常见的病因 疾病尽管早老素在20多年前就被鉴定参与阿尔茨海默病， 早老素突变的功能性后果尚不清楚。在这里，我们建议审查 SEL-12在C.了解其在钙处理和线粒体活性和增益中的作用 对阿尔茨海默病病理学的深入了解。因此，利用C.优雅的人，我们正在采取一个 利用活细胞成像与遗传、分子和细胞生物学技术相结合的多方面方法 为了验证以下假设：早老素/SEL-12的功能是调节内质网钙 信号传导，并且在缺乏早老素/SEL-12功能的情况下， 增加影响线粒体功能和细胞适应性。我们相信我们的研究将提供新的 了解阿尔茨海默病的机制，因此，将提供独特的见解 致力于开发治疗阿尔茨海默病的新策略。

Summary/Abstract Calcium, a versatile signaling molecule, is a critical mediator of many cellular processes, including muscle contraction, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium signaling can affect cells in different ways and to varying degrees. Consequently, calcium levels need to be tightly controlled. Indeed, defective calcium signaling has been implicated in many neurodegenerative diseases, muscular dystrophies and heart disease. To understand the regulation of calcium signaling, we are exploiting the model system Caenorhabditis elegans to identify critical components that are involved in the regulation of calcium handling. From our non-biased genetic studies, we have found a novel role for a conserved protein, SEL-12, in endoplasmic reticulum calcium handling which is critical for mitochondria morphological organization and function. SEL-12 is the C. elegans homolog of presenilin. Mutations in presenilins are the most common cause of early onset familial Alzheimer's disease. Despite the identification of the involvement of presenilin in Alzheimer's disease over 20 years ago, the functional consequences of mutations in presenilin are not understood. Here, we propose to examine the function of SEL-12 in C. elegans to understand its role in calcium handling and mitochondrial activity and gain insight into Alzheimer's disease pathology. Thus, using the strengths of the C. elegans, we are taking a multifaceted approach utilizing live cell imaging in concert with genetic, molecular and cell biology techniques to test the following hypothesis: Presenilin/SEL-12 functions to regulate endoplasmic reticulum calcium signaling and that in the absence of presenilin/SEL-12 function calcium transfer to the mitochondria is increased impacting mitochondrial function and cellular fitness. We believe our studies will provide novel understanding into the mechanisms that arise in Alzheimer's disease and will, therefore, provide unique insight into the development of new therapeutic strategies for Alzheimer's disease.