Correlating defects in mitochondrial DNA replication to physiology
将线粒体 DNA 复制缺陷与生理学相关联
基本信息
- 批准号:9206171
- 负责人:
- 金额:$ 35.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAdverse effectsAffectAge of OnsetAgingAllelesAlpers&apos SyndromeBiochemicalBiochemistryBiological AssayBiological ModelsBiomedical ResearchBirthCatalytic DomainCessation of lifeChemicalsClinicalComplexCoupledDNADNA SequenceDNA biosynthesisDNA copy numberDNA-Directed DNA PolymeraseData AnalysesDefectDiagnosisDiscriminationDiseaseEnzymesExcisionExonucleaseFrequenciesGenesGeneticGoalsGrowthGuidelinesHIV InfectionsHeritabilityHeterozygoteHumanImpairmentIn VitroKineticsKnowledgeLeadLearningLiteratureLiver diseasesMalignant NeoplasmsMeasurementMethodsMitochondriaMitochondrial DNAMitochondrial DiseasesModelingMolecularMonitorMuscleMutationMyopathyNuclearNucleotidesPatientsPeripheral Nervous System DiseasesPhenotypePhysiologicalPhysiologyPoint MutationPolymeraseProteinsPublishingReactionRefractoryResearchRoleSS DNA BPSeizuresSeveritiesSeverity of illnessSite-Directed MutagenesisSpeedStructureStructure-Activity RelationshipSymptomsSyndromeSystemToxic effectVirus DiseasesWorkYeast Model SystemYeastsaccurate diagnosisbaseclinical effectclinical phenotypeclinical predictorseffective therapyhelicasehuman DNAhuman diseasemutantnucleoside analogoxidative damagepolymerizationpublic health relevancereconstitutionskeletal
项目摘要
DESCRIPTION (provided by applicant): An important goal of biomedical research is to establish the molecular basis for disease so that more effective therapies can be devised. Relating the biochemical effects of heritable point mutations to their physiological and clinical consequences is a challenging but important step toward reaching this goal. Mutations in the human mitochondrial DNA (mtDNA) polymerase have been correlated with various mitochondrial disorders, including mtDNA depletion syndrome, Alpers Syndrome, and progressive external opthalmoplegia (PEO). Symptoms of Alpers Syndrome include liver disease and refractory seizures, while patients with PEO present with progressive weakness of the external ocular muscles and skeletal myopathy. Many of the nucleoside analogs used to treat viral infections have toxic side effects due to inhibition of mtDNA replication, which are seen first as peripheral neuropathy. Mitochondrial DNA replication is performed by a replisome comprised of a nuclearly-encoded DNA polymerase, processivity factor, single-stranded DNA binding protein (mtSSB), and DNA helicase. The major challenge in interpreting the clinical effects of mutations in the mtDNA polymerase lies in understanding the molecular basis for the slow onset of the symptoms. Like other heritable disorders of the mitochondrial genes and the toxic side effects of nucleoside analogs used to treat HIV infection, mutations in the mtDNA polymerase lead to diseases often characterized by slow onset due to the accumulation of mtDNA defects and oxidative damage, although certain mutations lead to more severe symptoms resulting in death within one to two years of birth. Understanding the clinical consequences of point mutations in the mtDNA polymerase requires precise and accurate measurements and rigorous data analysis. We will use site-directed mutagenesis and comprehensive kinetic analysis to evaluate the effects of mutations on the mtDNA polymerase in vitro. In addition, we will work to correlate changes in structure and function of the polymeras to the physiological consequences of these mutations observable in a humanized yeast model system expressing the human mtDNA polymerase, which appears to be a good model system to predict the long term consequences of mutations in humans. We will use single turnover rapid kinetic studies to directly examine reactions occurring at the active site in order to quantify key
kinetic parameters governing DNA replication. We will also work to examine the role of the mtDNA helicase and mtSSB in the coordinated DNA unwinding and leading strand synthesis. This research will provide a better understanding of the role of the mtDNA polymerase in diseases related to mitochondrial function, and will provide new information to define the molecular basis for nucleotide discrimination by the human mtDNA polymerase, the physiological basis for the toxicity of nucleoside analogs used to treat HIV infections, and the role of mtDNA polymerase and helicase mutations in heritable disorders.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KENNETH ALLEN JOHNSON其他文献
KENNETH ALLEN JOHNSON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KENNETH ALLEN JOHNSON', 18)}}的其他基金
Kinetic and structural basis for SARS-CoV-2 RNA-dependent RNA polymerase specificity and inhibition
SARS-CoV-2 RNA 依赖性 RNA 聚合酶特异性和抑制的动力学和结构基础
- 批准号:
10452645 - 财政年份:2021
- 资助金额:
$ 35.94万 - 项目类别:
Kinetic and structural basis for SARS-CoV-2 RNA-dependent RNA polymerase specificity and inhibition
SARS-CoV-2 RNA 依赖性 RNA 聚合酶特异性和抑制的动力学和结构基础
- 批准号:
10659068 - 财政年份:2021
- 资助金额:
$ 35.94万 - 项目类别:
Kinetic and structural basis for SARS-CoV-2 RNA-dependent RNA polymerase specificity and inhibition
SARS-CoV-2 RNA 依赖性 RNA 聚合酶特异性和抑制的动力学和结构基础
- 批准号:
10278189 - 财政年份:2021
- 资助金额:
$ 35.94万 - 项目类别:
Correlating defects in mitochondrial DNA replication to physiology
将线粒体 DNA 复制缺陷与生理学相关联
- 批准号:
8860390 - 财政年份:2015
- 资助金额:
$ 35.94万 - 项目类别:
Correlating defects in mitochondrial DNA replication to physiology
将线粒体 DNA 复制缺陷与生理学相关联
- 批准号:
9412492 - 财政年份:2015
- 资助金额:
$ 35.94万 - 项目类别:
Dynamics of Hepatis C viral RNA-dependent RNA replication
丙型肝炎病毒 RNA 依赖性 RNA 复制的动力学
- 批准号:
8967146 - 财政年份:2014
- 资助金额:
$ 35.94万 - 项目类别:
Nucleotide selectivity and drug resistance by HIV reverse transcriptase
HIV逆转录酶的核苷酸选择性和耐药性
- 批准号:
7930581 - 财政年份:2009
- 资助金额:
$ 35.94万 - 项目类别:
Nucleotide selectivity and drug resistance by HIV reverse transcriptase
HIV逆转录酶的核苷酸选择性和耐药性
- 批准号:
8306332 - 财政年份:2009
- 资助金额:
$ 35.94万 - 项目类别:
Nucleotide selectivity and drug resistance by HIV reverse transcriptase
HIV逆转录酶的核苷酸选择性和耐药性
- 批准号:
8117771 - 财政年份:2009
- 资助金额:
$ 35.94万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 35.94万 - 项目类别:
Research Grant