Deciphering Molecular Mechanisms of Calcium Homeostasis

破译钙稳态的分子机制

• 批准号: 10796459
• 负责人: Kenneth R Norman
• 金额: $ 18.47万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796459
• 关键词: Alzheimer' s Disease; Behavioral Assay; Biological Assay; Biological Models; Caenorhabditis elegans; Calcium; Calcium Signaling; Cell Death; Cell division; Cell physiology; Defect; Disease; Early Onset Familial Alzheimer' s Disease; Endoplasmic Reticulum; Functional disorder; Genetic Transcription; Goals; Health; Heart Diseases; Homeostasis; Human; Lysosomes; Mediating; Mediator; Meditation; Mitochondria; Molecular; Muscle Contraction; Muscular Dystrophies; Mutation; Necrosis; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Orthologous Gene; Plants; Process; Proteins; RNA interference screen; Regulation; Research Project Grants; Resolution; Role; Structure; Synaptic Vesicles; System; age related; cell type; fitness; gene product; genetic manipulation; insight; live cell microscopy; mitochondrial metabolism; mutant; novel; presenilin; proteostasis; uptake; vesicular release

PROJECT SUMMARY/ABSTRACT Calcium is a critical mediator of many cellular processes, including muscle contraction, mitochondrial activity, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium signaling can disrupt cellular homeostasis. 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 mechanisms regulating calcium signaling and how defects in this process can lead to cellular dysfunction, we are exploiting the model system Caenorhabditis elegans to identify critical processes that are involved in the regulation of calcium handling. We have recently demonstrated that SEL-12, the C. elegans presenilin ortholog, has a role in mediating endoplasmic reticulum-mitochondrial calcium homeostasis. Disruption of presenilin function results in an increase in mitochondrial calcium levels and alters mitochondrial metabolism promoting protein homeostasis collapse and neurodegeneration. Presenilin is a highly conserved protein found from plants to humans that is extensively found on endomembrane structures (e.g., endoplasmic reticulum and lysosome) of most cell types. However, the role presenilin has in the endomembrane system is not clear. Importantly, mutations in human presenilin 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 causing Alzheimer's disease are not understood. To gain further insight into the role presenilin has in mitochondrial calcium homeostasis and neuronal fitness, we have developed a novel and highly selective RNA interference screen to identify gene products that meditate the elevated endoplasmic reticulum to mitochondrial calcium signaling observed in sel-12 mutants. From this screen, we have identified several proteins known to mediate endoplasmic reticulum calcium release and mitochondrial calcium uptake but we also identified several gene products with an uncharacterized role in endoplasmic reticulum and mitochondrial calcium signaling. We propose to utilize a multifaceted approach that combines genetic manipulation, high resolution live cell microscopy to analyze endoplasmic reticulum and mitochondrial dynamics, mitochondrial activity assays, and behavioral assays to determine the role these gene products as well as sel- 12 have in mitochondrial health and neuronal fitness.

项目总结/文摘