Systems analysis of mitochondrial genome maintenance in physiological context

生理背景下线粒体基因组维护的系统分析

• 批准号: 10500906
• 负责人: Samantha C Lewis
• 金额: $ 37.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10500906
• 关键词: ATP Synthesis Pathway; Alleles; Animals; Biology; Cell Maintenance; Cell physiology; Cells; Cellular biology; Chromosomes; Complex; DNA biosynthesis; DNA copy number; Disease; Eukaryotic Cell; Fostering; Genetic Transcription; Genome; Goals; Health; Heritability; Homeostasis; Human; Invertebrates; Lead; Literature; Maintenance; Malignant Neoplasms; Metabolic Diseases; Microscopy; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Inheritance; Mitochondrial Respiratory Chain Deficiencies; Modeling; Molecular; Nerve Degeneration; Organelles; Oxidative Phosphorylation; Pathway interactions; Physiological; Process; Proteins; Proteomics; RNA; Research; Somatic Cell; Systems Analysis; Tissues; United States National Institutes of Health; Work; experimental study; human disease; insight; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mutant; new therapeutic target; novel; segregation; targeted treatment

Project Description/Summary Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. However, the pathways that regulate mtDNA synthesis and segregation in animal cells are not well understood. The goals of this work are to identify the protein components of mitochondrial DNA nucleoid complexes, to investigate how mitochondrial replication and dynamics are coordinated to homeostatically maintain mtDNA nucleoid segregation and abundance, and to probe the mechanisms underlying selection against mutant mtDNAs in somatic cells. These experiments will provide fundamental insights into the maintenance of the essential mitochondrial chromosome in animal cells and how maintenance processes are regulated, potentially leading to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA disease alleles. We will employ cutting-edge microscopy of living cells and whole animals, proteomics, and single cell transcriptional analyses to interrogate the molecular functions of candidate proteins implicated in the maintenance of mtDNA integrity. These experiments will reconcile inconsistencies in the mitochondrial biology literature, provide fundamental insight into the mechanisms of mtDNA copy number control, and identify novel pathways that regulate the tissue-specific manifestations of mitochondrial dysfunction.

项目描述/总结