MutSensor System: A Set of Highly Sensitive Mutation Reporters to Dissect Genome Stability in Health and Disease
MutSensor 系统:一组高度灵敏的突变报告基因,用于剖析健康和疾病中基因组的稳定性
基本信息
- 批准号:10737167
- 负责人:
- 金额:$ 75.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-15 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:BindingBiological AssayCarcinogensCell LineCellsChromosome MappingClustered Regularly Interspaced Short Palindromic RepeatsCodeCommunitiesDNA DamageDNA RepairDNA Sequence AlterationDNA cassetteDataDiseaseEventExposure toFamilyFrequenciesGenesGeneticGenetic DeterminismGenetic ScreeningGenetic studyGenomeGenome StabilityGerm-Line MutationGoalsGuide RNAHCT116 CellsHealthHumanHuman bodyIndividualInduced MutationKnowledgeLaboratoriesLeadLeftLibrariesLocationMalignant NeoplasmsMammalian CellMethodologyMethodsMismatch RepairMutagenesisMutagensMutateMutationMutation DetectionOpen Reading FramesPathway interactionsPharmaceutical PreparationsPoint MutationProcessProteinsReporterRepressionResistanceShapesSignal TransductionSingle Nucleotide PolymorphismSiteSortingSystemTestingTimeTissuesVariantWritingYeastscarcinogenesiscell typedesignexperimental studyfollow-upgain of functiongenetic approachgenome integritygenome-widehuman diseasehuman tissueinnovationloss of functionloss of function mutationmodel organismmutantnoveloverexpressionpromoterprototypescreeningsensortoolvariant detection
项目摘要
Summary
Our cells are constantly exposed to mutagens that cause DNA damage, which if left unrepaired, cause mutations.
At the cellular level, the progressive accumulation of mutations in somatic tissues drives carcinogenesis and
other diseases. Despite significant advances in our understanding of mutational processes, the answer to many
fundamental questions is still a mystery. What are the genetic causes of mutations in human tissues? How
do different cell types in the human body control DNA damage and repair? Despite our large body of
knowledge in the pathways that control DNA damage and repair in model organisms, we lack a deep
understanding of this process in human tissues. This would be critical to understand how mutations lead to
human diseases including carcinogenesis.
Here we will use a highly innovative approach to build MutSensor, a set of mutation reporters to estimate
DNA mutation frequency in mammalian cells with a sensitivity >50-fold higher than that of existing
methods. The ability to build and precision deliver these MutSensors is enabled by “Genetic Writing and
Delivery” system developed in the Boeke lab. This novel method will allow large-scale functional genetic
screening at an unprecedented scale. Building on our preliminary data, we aim at comprehensively identify all
genes that regulate mutation frequency in different human cell types. To this purpose, we will utilize loss- and
gain-of-function screening libraries to determine the effect of genetic perturbations on mutation frequency across
cell types.
These studies will provide an unprecedented systematic map of genes and pathways controlling DNA damage
and mutations across different human cell types. In addition, our novel methodology will represent an important
asset for the scientific community that can have several biomedical applications in a variety of fields
providing an easy tool to study genetic factors that control mutagenesis in health and disease states,
including (but not limited to) carcinogenesis.
总结
我们的细胞不断暴露于诱变剂,导致DNA损伤,如果不修复,就会导致突变。
在细胞水平上,突变在体细胞组织中的进行性积累驱动癌发生,
其它疾病尽管我们对突变过程的理解取得了重大进展,但许多问题的答案仍然是未知的。
基本问题仍然是个谜。人体组织突变的遗传原因是什么?如何
人体内不同类型的细胞控制DNA损伤和修复吗?尽管我们的庞大的身体
在控制模式生物中DNA损伤和修复的途径方面,我们缺乏深入的知识,
了解人体组织中的这一过程。这对于理解突变如何导致
人类疾病,包括癌症。
在这里,我们将使用一种高度创新的方法来构建MutSensor,这是一组突变报告基因,
哺乳动物细胞中的DNA突变频率,灵敏度比现有的
方法.构建和精确提供这些MutSensors的能力是通过“基因书写和
在伯克实验室研发的“传送”系统。这种新的方法将允许大规模的功能性遗传
以前所未有的规模进行筛选。根据我们的初步数据,我们的目标是全面确定所有
调节不同人类细胞类型突变频率的基因。为此,我们将利用损失-和
功能获得筛选文库,以确定遗传扰动对突变频率的影响,
细胞类型。
这些研究将为控制DNA损伤的基因和途径提供前所未有的系统图谱
和不同人类细胞类型的突变。此外,我们的新方法将代表一个重要的
这是科学界的一项资产,可以在各种领域中进行多种生物医学应用
提供了一种简单的工具来研究控制健康和疾病状态下诱变的遗传因素,
包括(但不限于)致癌作用。
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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Jef D BOEKE其他文献
Jef D BOEKE的其他文献
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{{ truncateString('Jef D BOEKE', 18)}}的其他基金
Brca1-Mediated Suppression Of Retrotransposon Activity - Resubmission - 1
Brca1 介导的逆转录转座子活性抑制 - 重新提交 - 1
- 批准号:
9979202 - 财政年份:2020
- 资助金额:
$ 75.84万 - 项目类别:
Supplement for Center for Synthetic Regulatory Genomics: Building CACNA1C alleles associated with Neuropsychiatric Disorders
合成调控基因组学中心的补充:构建与神经精神疾病相关的 CACNA1C 等位基因
- 批准号:
10405299 - 财政年份:2018
- 资助金额:
$ 75.84万 - 项目类别:
CEGS: Center for Synthetic Regulatory Genomics - Renewal
CEGS:合成监管基因组学中心 - 更新
- 批准号:
10652025 - 财政年份:2018
- 资助金额:
$ 75.84万 - 项目类别:
Core B - Retrotransposon Genomics, Technology and Analysis Core
核心 B - 逆转录转座子基因组学、技术和分析核心
- 批准号:
10581511 - 财政年份:2016
- 资助金额:
$ 75.84万 - 项目类别:
Core B - Retrotransposon Genomics, Technology and Analysis Core
核心 B - 逆转录转座子基因组学、技术和分析核心
- 批准号:
10333659 - 财政年份:2016
- 资助金额:
$ 75.84万 - 项目类别:
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