Harnessing Supercoiling to Regulate DNA Activity
利用超螺旋调节 DNA 活性
基本信息
- 批准号:10482361
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAntibioticsAntineoplastic AgentsArtsBindingBiochemicalBiological AssayBiophysicsCell physiologyCellsChromatin LoopCoupledCryoelectron MicroscopyDNADNA StructureDNA TopoisomerasesDNA biosynthesisDataDrug InteractionsDrug TargetingEngineeringEnzymesFluorescenceFrequenciesGene DeliveryGene Transduction AgentGenetic TranscriptionGenomic InstabilityGoldHumanImaging DeviceInfectionKnowledgeLibrariesMalignant NeoplasmsMethodsMolecular ConformationMonosaccharidesPharmaceutical PreparationsPhysiologicalPropertyResearchSculptureShapesStructureSuperhelical DNATechniquesTextbooksTherapeuticTimeTopoisomeraseVisionWorkanalytical ultracentrifugationantimicrobial drugclinical applicationdesign and constructiondrug actiondrug efficacyexperimental studyfundamental researchgene therapyhuman diseaseimprovedin vivoinhibitorinnovationinsightnanoparticlenervous system disordernovelnovel therapeuticsrepairedscreeningtargeted agentthree dimensional structuretomographytooluptake
项目摘要
This MIRA proposal presents my vision for how my research will evolve over the next five years and
culminates from our long-term, rigorous studies of the diverse structures and properties of supercoiled DNA
and its interaction with topoisomerases. Within cells, DNA is supercoiled and often constrained into small DNA
loops that can be experimentally recapitulated with supercoiled DNA minicircles small enough for use in a wide
range of biophysical and biochemical assays. The methods we have developed and extensive knowledge
acquired thus far will be invaluable for our proposed studies of DNA topoisomerases, actions of important
antimicrobial and anticancer agents that target them, the utility of engineered DNA minicircles as gene therapy
vectors, and supercoiling-induced noncanonical DNA structures that are implicated in human disease. We will
first utilize state-of-the-art electron cryo-microscopy and cryo-tomography to determine the 3-D structure of
topoisomerases bound to physiologically relevant DNA substrates. This approach will be coupled with
comprehensive quantitative assays using electrophoretic and fluorescence techniques and analytical
ultracentrifugation to characterize how DNA supercoiling so strongly affects topoisomerase-drug interactions.
Many topoisomerases, particularly those that are important drug targets, preferentially act on positively
supercoiled DNA. Consequently, corresponding anti-topoisomerase drugs interact with positively supercoiled
DNA as well, although research of chemotherapeutics that target topoisomerases has largely disregarded the
effect of supercoiled DNA on drug action. We plan to identify new inhibitors of validated drug targets by
screening, for the first time, active topoisomerase bound to positively supercoiled DNA against a library of over
5 billion diverse compounds. We will next apply our innovative tools and compelling data of how supercoiling,
curvature, and sequence dictate DNA conformation to design and construct DNA nanoparticles with specific,
desired shapes that are ideal for cellular uptake needed in a variety of clinical applications. Existing
nanoparticles, such as those composed of gold or monosaccharides, are inert; therefore, we propose utilizing
DNA minicircles, as both the vehicle and cargo in one, for gene therapy to overcome many of the barriers to
effective gene delivery. Finally, we will employ DNA minicircles to investigate how supercoiling promotes the
formation of non-B-DNA structures, which are known to impact DNA replication, repair, transcription, yet their
in vivo frequency is controversial. This work is transformative, as our novel DNA minicircles, advanced imaging
tools, and quantitative analyses will enable us to achieve unprecedented and previously unattainable insights
into the structure and function of supercoiled DNA. Our fundamental research will continue to challenge the
paradigm that DNA is passively acted upon by topoisomerases but instead drives numerous critical cellular
processes. Moreover, this project has substantial human therapeutic applications related to anti-topoisomerase
drug efficacy, improved gene therapy delivery, and mitigating genomic instability caused by non-B-DNA forms.
这个MIRA提案展示了我对未来五年我的研究将如何发展的愿景
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)
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LYNN ZECHIEDRICH其他文献
LYNN ZECHIEDRICH的其他文献
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{{ truncateString('LYNN ZECHIEDRICH', 18)}}的其他基金
Harnessing Supercoiling to Regulate DNA Activity
利用超螺旋调节 DNA 活性
- 批准号:
10205924 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Harnessing Supercoiling to Regulate DNA Activity
利用超螺旋调节 DNA 活性
- 批准号:
10705655 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Harnessing Supercoiling to Regulate DNA Activity
利用超螺旋调节 DNA 活性
- 批准号:
10798577 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Molecular Mechanisms Underlying Fluoroquinolone Susceptibility and Resistance
氟喹诺酮类药物敏感性和耐药性的分子机制
- 批准号:
8941338 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
S2: Molecular Mechanisms Underlying Fluoroquinolone Susceptibility and Resistance
S2:氟喹诺酮类药物敏感性和耐药性的分子机制
- 批准号:
9539894 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
Molecular Mechanisms Underlying Fluoroquinolone Susceptibility and Resistance
氟喹诺酮类药物敏感性和耐药性的分子机制
- 批准号:
9276741 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
Molecular Mechanisms Underlying Fluoroquinolone Susceptibility and Resistance
氟喹诺酮类药物敏感性和耐药性的分子机制
- 批准号:
9276456 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
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