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Investigation of Calcium Signaling in Caenorhabditis elegans

秀丽隐杆线虫钙信号传导的研究

基本信息

批准号：
9353426
负责人：
Kenneth R Norman
金额：
$ 31.6万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353426
关键词：
Abeta synthesis Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Area Attenuated Biological Models Caenorhabditis elegans Calcium Calcium Signaling Candidate Disease Gene Cell Death Cell division Cell physiology Cells Cellular biology Communication Data Defect Dementia Development Early Onset Familial Alzheimer&apos s Disease Endoplasmic Reticulum Failure Functional disorder Genes Genetic Genetic Screening Genetic Transcription Genetic study Goals Heart Diseases Homeostasis Homologous Gene Impaired cognition Investigation Lead Mediator of activation protein Membrane Memory Loss Mitochondria Molecular Molecular Biology Morphology Muscle Contraction Muscular Dystrophies Mutation Necrosis Nervous system structure Neurodegenerative Disorders Neurologic Neurons Pathology Process Proteins Regulation Research Role Signal Transduction Signaling Molecule Structure Symptoms Synaptic Vesicles Techniques Testing Therapeutic Trials base fitness gene product innovation insight live cell imaging mitochondrial dysfunction mutant novel novel therapeutic intervention presenilin trafficking vesicular release

项目摘要

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.

钙是一种多功能的信号分子，是许多细胞过程的关键媒介，包括肌肉。收缩、转录、细胞分裂和突触小泡释放。矛盾的是，钙也能触发细胞死亡和细胞坏死。因此，钙信号的失调可以通过不同的方式影响细胞和程度各不相同。因此，需要严格控制钙水平。事实上，有缺陷的钙信号转导与许多神经退行性疾病、肌营养不良症和心脏病有关。为了了解钙信号的调节，我们利用模型系统秀丽线虫。确定与钙处理调节有关的关键成分。从我们不带偏见的在遗传学研究中，我们发现了一种保守的蛋白质SEL-12在内质网钙离子中的新作用处理对线粒体的形态组织和功能至关重要。SEL-12是线虫早老素的同系物。早老素基因突变是早发性家族性阿尔茨海默病最常见的原因疾病。尽管早在20多年前就发现早老素与阿尔茨海默病有关，早老素突变的功能后果尚不清楚。在这里，我们建议研究 SEL-12在线虫中的功能了解其在钙转运和线粒体活性和增益中的作用对阿尔茨海默病病理的洞察。因此，利用线虫的优势，我们正在采取一种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验证以下假说：早老素/SEL-12对内质网钙的调节作用信号转导和在没有早老素/SEL-12功能的情况下钙离子转移到线粒体是增加了对线粒体功能和细胞健康的影响。我们相信我们的研究将为我们提供新的对阿尔茨海默病发病机制的理解将提供独特的洞察力致力于阿尔茨海默病新治疗策略的开发。