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Molecular mechanisms of mtDNA inheritance

线粒体DNA遗传的分子机制

基本信息

批准号：
10085799
负责人：
Samantha C Lewis
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-07 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10085799
关键词：
ATP Synthesis Pathway Acute Address Alleles Attenuated Bar Codes Biology Buffers CRISPR interference Cell physiology Cells Cellular biology Circular DNA Critical Pathways DNA DNA Maintenance DNA biosynthesis DNA copy number Data Disease Endoplasmic Reticulum Escherichia coli Estrogen receptor positive Etiology Eukaryotic Cell Event Fostering Gene Cluster Genes Genetic Genetic Transcription Genome Goals Growth Haplotypes Heritability High-Throughput Nucleotide Sequencing Human Individual Laboratories Lead Libraries Link Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Mediating Metabolic Diseases Microscopy Microtubules Mission Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Inheritance Mitochondrial Respiratory Chain Deficiencies Molecular Mutation Nerve Degeneration Organelles Oxidative Phosphorylation Pathway interactions Postdoctoral Fellow Process Proteins Proteomics RNA Recovery Regulation Research Research Personnel Residual state Role Science Severity of illness Site Structure System Technology Testing Tissues Topoisomerase Topoisomerase III United States National Institutes of Health Viral Work Zalcitabine antiviral nucleoside analog base cell growth cell motility cell type cohort comparative constriction disease phenotype experimental study genome wide screen genome-wide human disease insight knock-down live cell microscopy mitochondrial DNA mutation mitochondrial genome mutant new therapeutic target novel nuclease professor respiratory response segregation single molecule real time sequencing single-cell RNA sequencing targeted treatment transcriptome sequencing

项目摘要

Project Summary Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. However, pathways that control mtDNA segregation and copynumber in mammalian cells are not well understood. The goals of this work are to identify and characterize the unknown protein machinery that segregates replicating mtDNAs into discrete nucleoid structures at ER-mitochondria contact sites and to describe the mechanisms and pathways that regulate mtDNA copy number. The proposed experiments will provide fundamental insight into the mechanism of mtDNA segregation and copynumber control, and how those processes are regulated, potentially leading to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA disease haplotypes. In Aim 1, cutting-edge live-cell microscopy, proteomics, and high-throughput sequencing technologies will be employed to dissect the molecular functions of mtDNA segrosome candidate proteins identified in preliminary experiments. Aim 2 will address which cellular pathways are critical to regulation of mtDNA copy number in human cells. This will be accomplished by systematic genome-wide screens for modulators of mtDNA depletion recovery, single-cell RNA sequencing to cluster genes by their transcriptional responses to mtDNA loss, and the characterization of candidate mtDNA copynumber effector proteins in human cells depleted of mtDNA. These experiments will provide fundamental insight into the mechanism of mtDNA segregation and copynumber control, and how those processes are regulated, potentially leading to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA disease haplotypes.

项目总结