Genetic dissection of oncogenic RAS-driven tumor initiation in vivo
体内致癌 RAS 驱动的肿瘤发生的基因剖析
基本信息
- 批准号:10610444
- 负责人:
- 金额:$ 46.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAllelesBacteriaBiological AssayBiological ModelsBiologyCancer BiologyCancer PatientCarcinogen exposureCellsClinicalDataDiseaseDissectionEarly DiagnosisEngineeringEventFamilyFrequenciesGenesGeneticGenetic InductionGenetically Engineered MouseGoalsHumanIndividualInduced MutationInvestigationKRAS oncogenesisKRAS2 geneLesionLungMalignant NeoplasmsMethodsModelingMonitorMusMutagenesisMutateMutationNatureNormal CellOncogenesOncogenicPathologic MutagenesisPatternPopulationPositioning AttributePreventionProcessProtein IsoformsProteinsPublishingRAS driven tumorRAS genesRefractoryReportingSeveritiesSignal TransductionTissuesTumor-Associated ProcessUrethanecancer initiationcancer typecarcinogenesiscell typeclinically relevantde novo mutationin vivoindividual responseinnovative technologiesinsightmouse modelmutantnext generation sequencingnovelpotential biomarkerpreventresponsesingle-cell RNA sequencingtherapeutic targettumortumor initiationtumorigenesistumorigenic
项目摘要
PROJECT SUMMARY/ABSTRACT
The RAS family comprised of KRAS, NRAS, and HRAS are the most commonly mutated oncogenes in human
cancer. Despite there being over 50 possible oncogenic RAS mutations, each cancer type has a specific and
often unique subset of these mutations. As RAS mutations typically occur early during tumorigenesis, if not
being the initiating mutation, these mutational patterns reflect fundamental biology underlying the process of
tumor initiation. Elucidating the mechanisms giving rise to RAS mutation patterns would therefore address
a foundational question in cancer biology- how cancer originates. Given this, the most informative approach to
interrogate these patterns is to study RAS mutations when they 1) first occur in 2) normal cells in an 3) in vivo
setting. Trying to backtrack to catch that one random mutagenic event in one gene from one cell that initiates
cancer decades before manifesting as a disease is challenging in humans. There are, however, two murine
model systems that allow an initiating RAS mutation to be precisely defined, and hence are amenable to studying
RAS mutation patterns. One, carcinogenesis, which is particularly well suited to interrogate how the mutagenic
process gives rise to RAS mutation patterns. Two, genetic activation of mutant alleles in a spatially and
temporally restricted fashion, which is ideal to study the response of defined Ras mutations in normal cells. We
thus propose to capitalize on the individual strengths of these two different models to elucidate the mechanisms
by which RAS mutation patterns are laid down in normal cells at the very onset of tumorigenesis in vivo.
Specifically, in aim 1 we will determine how tumors arise by a specific Ras mutation by monitoring mutagenesis
immediately after carcinogen exposure and thereafter in genetic backgrounds that alter RAS mutation patterns.
In aim 2 we will determine the signaling and cellular responses of different normal cells upon genetic induction
of different oncogenic Ras mutants. Completion of this proposal will thus elucidate the principles underlying the
selection for specific RAS mutations in human cancers, and more broadly, how cancers originate, which has
clinical implications for early detection and prevention.
项目总结/摘要
RAS家族由KRAS、NRAS和HRAS组成,是人类中最常见的突变癌基因
癌尽管存在超过50种可能的致癌RAS突变,但每种癌症类型都具有特定的
通常是这些突变的独特子集。由于RAS突变通常发生在肿瘤发生的早期,如果不是,
作为起始突变,这些突变模式反映了
肿瘤起始。因此,阐明RAS突变模式的产生机制将解决
癌症生物学的一个基本问题癌症是如何起源的鉴于此,最翔实的方法,
研究这些模式是为了研究RAS突变何时1)首先发生在2)正常细胞中3)在体内
设置.试图回溯到一个细胞的一个基因中的一个随机突变事件,
癌症在表现为疾病之前几十年对人类具有挑战性。然而,有两个鼠
模型系统,允许启动RAS突变被精确定义,因此适合研究
RAS突变模式。第一,致癌作用,这特别适合于研究
过程产生RAS突变模式。第二,突变等位基因在空间和
时间限制的方式,这是理想的研究定义的Ras突变在正常细胞中的响应。我们
因此,建议利用这两种不同模型的各自优势来阐明机制
其中RAS突变模式在体内肿瘤发生的最开始时就在正常细胞中奠定。
具体来说,在目标1中,我们将通过监测诱变来确定特定Ras突变如何引起肿瘤
在致癌物暴露后立即和此后在改变RAS突变模式的遗传背景中。
在目标2中,我们将确定不同的正常细胞在遗传诱导后的信号传导和细胞反应
不同的致癌Ras突变体。因此,完成这一建议将阐明
选择人类癌症中的特定RAS突变,更广泛地说,癌症是如何起源的,
对早期发现和预防的临床意义。
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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CHRISTOPHER M COUNTER其他文献
CHRISTOPHER M COUNTER的其他文献
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{{ truncateString('CHRISTOPHER M COUNTER', 18)}}的其他基金
Proteasomal recruiters of PAX3-FOXO1 Designed via Sequence-Based Generative Models
通过基于序列的生成模型设计的 PAX3-FOXO1 蛋白酶体招募剂
- 批准号:
10826068 - 财政年份:2023
- 资助金额:
$ 46.84万 - 项目类别:
Screening for Cys-Reactive Ligands to Target PAX3-FOXO1
筛选针对 PAX3-FOXO1 的 Cys 反应性配体
- 批准号:
10611002 - 财政年份:2022
- 资助金额:
$ 46.84万 - 项目类别:
Genetic dissection of oncogenic RAS-driven tumor initiation in vivo
体内致癌 RAS 驱动的肿瘤发生的基因剖析
- 批准号:
10415753 - 财政年份:2022
- 资助金额:
$ 46.84万 - 项目类别:
Defining and targeting the molecular vulnerabilities of the PAX3-FOXO1 protein in rhabdomyosarcoma
横纹肌肉瘤中 PAX3-FOXO1 蛋白的分子脆弱性的定义和靶向
- 批准号:
10221086 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Defining and targeting the molecular vulnerabilities of the PAX3-FOXO1 protein in rhabdomyosarcoma
横纹肌肉瘤中 PAX3-FOXO1 蛋白的分子脆弱性的定义和靶向
- 批准号:
10221081 - 财政年份:2020
- 资助金额:
$ 46.84万 - 项目类别:
Project 4: The role of codon bias in RAS tumorigenesis
项目 4:密码子偏倚在 RAS 肿瘤发生中的作用
- 批准号:
9074410 - 财政年份:2016
- 资助金额:
$ 46.84万 - 项目类别:
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