Targeting ER-mitochondrial calcium signaling to promote healthier aging

靶向 ER 线粒体钙信号传导以促进更健康的衰老

• 批准号: 10443143
• 负责人: Kristopher Burkewitz
• 金额: $ 32.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443143
• 关键词: Age of Onset; Aging; Alzheimer' s Disease; Anatomy; Animals; Behavior; Bioenergetics; Biological; Caenorhabditis elegans; Calcium; Calcium Signaling; Cardiovascular Diseases; Cells; Communication; Complex; Coupled; Data; Defect; Diabetes Mellitus; Disease; Electron Transport; Endoplasmic Reticulum; Engineering; Foundations; Functional disorder; Gene Expression; Genetic; Goals; Health; Homeostasis; Impairment; Inositol; Intervention; Lead; Life; Link; Longevity; Longevity Pathway; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Membrane; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Morphology; Neurons; Onset of illness; Organelles; Pathology; Pathway interactions; Physiological; Porifera; Process; Proteomics; Public Health; Regulation; Role; Rough endoplasmic reticulum; Shapes; Signal Transduction; Site; Structure; Study models; Testing; Tissues; Work; age related; aged; base; cell type; experimental study; genetic analysis; genetic manipulation; healthspan; mitochondrial dysfunction; mitochondrial fitness; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; receptor; release of sequestered calcium ion into cytoplasm; spatiotemporal; therapeutic target; tripolyphosphate

Project Summary/Abstract Fundamental gaps remain in our understanding of the cell biological mechanisms that drive mitochondrial decline and associated age-related diseases. Organelles like the mitochondria and endoplasmic reticulum (ER) are physically and functionally linked, in part via sites of membrane contact. These lines of communication between mitochondria and other organelles represent an understudied avenue by which to therapeutically target mitochondrial function. Our long-term goal is to understand the physiological roles of inter-organelle communication during aging and age-related disease. In pursuit of that goal, our objective in this application is to determine how the ER regulates mitochondrial health during aging through its role as a platform for calcium signaling. We have exploited the simple anatomy of C. elegans and experimental advantages in genetics and microscopy to lay a foundation in this model for the study of ER-mitochondrial interactions. Similar to mammals, the worm ER calcium efflux channel, inositol triphosphate receptor (InsP3R), exerts potent control over mitochondrial bioenergetics, and we have extended the roles of InsP3R to regulation of mitochondrial gene expression and dynamics in the worm as well. Furthermore, the InsP3R regulates lifespan in C. elegans through mechanisms that depend upon mitochondrial function. Here we will test the hypothesis that ER remodeling in aging animals acts to trigger mitochondrial dysfunction and organismal decline by promoting aberrant subcellular calcium signaling and dynamics. To test this hypothesis, we will first determine whether the InsP3R is a cell autonomous regulator of mitochondrial function and lifespan. Secondly, we will identify the molecular mechanisms linking InsP3R activity to the diverse changes observed in mitochondrial behavior. Finally, we will determine how organellar remodeling of the calcium flux machineries initiates age-onset mitochondrial dysfunction. By revealing the mechanisms by which ER signaling governs mitochondrial health at the organismal level, these results will open new therapeutic avenues in treating mitochondrial pathologies.

项目摘要/摘要 我们对驱动线粒体下降的细胞生物学机制的理解仍然存在基本差距 和与年龄有关的疾病。线粒体和内质网（ER）等细胞器是 物理和功能上的链接，部分通过膜接触部位。这些交流之间 线粒体和其他细胞器代表了一条研究的大街 线粒体功能。我们的长期目标是了解轨道间的生理作用 衰老和与年龄有关的疾病期间的交流。为了实现这一目标，我们在此应用中的目标是 确定急诊室如何通过其作为钙的平台来调节线粒体健康 信号。我们利用了秀丽隐杆线虫的简单解剖学以及遗传学和实验优势 显微镜奠定了该模型中的基础，以研究ER-线粒体相互作用。与哺乳动物类似 蠕虫ER钙外排信道，肌醇三磷酸受体（INSP3R），对 线粒体生物能学，我们将INSP3R的作用扩展到线粒体基因的调节 蠕虫的表达和动态。此外，INSP3R通过 取决于线粒体功能的机制。在这里，我们将测试重塑的假设 衰老动物的作用是通过促进异常亚细胞来触发线粒体功能障碍和有机体下降 钙信号传导和动力学。为了检验该假设，我们将首先确定INSP3R是否为单元 线粒体功能和寿命的自主调节剂。其次，我们将确定分子 将INSP3R活性与线粒体行为中观察到的不同变化联系起来的机制。最后，我们会的 确定钙通量机器的细胞器重塑如何启动年龄发作的线粒体 功能障碍。通过揭示ER信号在生物体中控制线粒体健康的机制 水平，这些结果将在治疗线粒体病理方面开放新的治疗途径。