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Investigating the Molecular Mechanisms of Mitochondrial Calcium Uptake in Caenorhabditis elegans

研究秀丽隐杆线虫线粒体钙摄取的分子机制

基本信息

批准号：
10456980
负责人：
Kenneth R Norman
金额：
$ 24.45万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456980
关键词：
Ablation Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyotrophic Lateral Sclerosis Animal Model Behavior Biological Models Buffers Caenorhabditis elegans Calcium Calcium Signaling Candidate Disease Gene Cell Death Cell physiology Citric Acid Cycle Complex Data Defect Development Disease Disease model Financial Hardship Foundations Gatekeeping Generations Genes Genetic Genetic Screening Goals Health Homeostasis Human Knock-out Mediating Mission Mitochondria Molecular Mutation Nerve Degeneration Neurodegenerative Disorders Organelles Output Oxidative Phosphorylation Oxidative Stress Parkinson Disease Pathologic Pathology Phylogenetic Analysis Population Production Proteins Reactive Oxygen Species Research Research Proposals Role Signaling Molecule Stress United States National Institutes of Health calcium uniporter common symptom design familial Alzheimer disease gene product improved in vivo Model innovation insight mitochondrial dysfunction mutant novel therapeutic intervention presenilin prevent research and development therapeutic target uptake

项目摘要

PROJECT SUMMARY The enormous societal burden caused by neurodegenerative disorders, stresses the importance of determining the underlying pathological mechanisms that promote disease. Both deregulated calcium signaling and disrupted mitochondrial function are a common symptom observed in neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. However, the underlying role these defects have in mediating pathology and if they impact each other to promote disease is not fully understood. In addition to their role in energy production, mitochondria function to sequester large influxes of cytosolic calcium and act as an organellular calcium buffer. However, the influx of calcium into the mitochondrial also stimulates the activity of the mitochondria, such as the tricarboxylic acid cycle, oxidative phosphorylation, the production of reactive oxygen species, and it can also trigger cell death. The phylogenetically conserved mitochondrial calcium uniporter complex mediates the uptake of calcium into the mitochondria. With the recent molecular identification of mitochondrial calcium uniporter complex components, many current studies have implicated altered mitochondrial calcium homeostasis as having a fundamental role in promoting neurodegeneration. These data highlight the importance of understanding the mechanisms that mediate mitochondrial calcium homeostasis. Here, we propose to utilize the genetic amenability and simplicity of C. elegans to 1) interrogate the role of the four core components of the mitochondrial calcium uniporter complex in an in vivo model system to establish a foundation of mitochondrial calcium uniporter complex function and to 2) discover new gene products that are involved in mitochondrial calcium influx. From these studies, our goals are to improve our understanding of mitochondrial calcium uptake and homeostasis and to provide critical guidance for the development of novel therapeutic strategies for treating neurodegenerative diseases.

项目总结神经退行性疾病造成的巨大社会负担，强调了确定促进疾病的潜在病理机制。两种钙信号都被解除了调控线粒体功能紊乱是神经退行性疾病的常见症状，包括肌萎缩侧索硬化症、帕金森氏病和阿尔茨海默病。然而，潜在的这些缺陷在介导病理过程中的作用，如果它们相互影响而促进疾病是不充分的明白了。除了在能量生产中的作用外，线粒体还具有隔离大量涌入的胞内钙，并作为细胞内钙的缓冲剂。然而，钙的流入线粒体还能刺激线粒体的活动，如三羧酸循环、氧化磷酸化，产生活性氧物种，它也可以引发细胞死亡。这个系统发育保守的线粒体钙单转运体复合体介导钙的摄取线粒体。随着最近对线粒体钙单转运体复合体成分的分子鉴定，目前的许多研究表明，线粒体钙稳态的改变具有基础性作用在促进神经退化方面。这些数据突出了了解以下机制的重要性调节线粒体钙动态平衡。在这里，我们建议利用基因的舒适性和简单性研究线粒体钙单一转运蛋白的四个核心成分的作用体内模型系统中的复合体建立线粒体钙单转运体复合体的基础 2)发现参与线粒体钙内流的新基因产物。从这些研究，我们的目标是提高我们对线粒体钙摄取和动态平衡的理解，并为开发治疗神经退行性变的新治疗策略提供关键指导疾病。