Decoding glioma evolution and progression by multi-dimensional single-cell profiling
通过多维单细胞分析解码神经胶质瘤的进化和进展
基本信息
- 批准号:10284709
- 负责人:
- 金额:$ 13.04万
- 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:2021-08-05 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAutomobile DrivingBar CodesBiological AssayCancer BiologyCatalogsCellsClassificationClinicClinicalClinical DataCommunitiesDNADNA MethylationDNA Sequence AlterationDataDetectionDevelopment PlansDiagnosisDiagnosticDiffuseDimensionsDiseaseDisease ProgressionDoctor of PhilosophyEnvironmentEpigenetic ProcessEventEvolutionGene ExpressionGene Expression ProfileGene TargetingGeneticGenetic TranscriptionGenetic studyGenomeGenotypeGlioblastomaGliomaGoalsGrowthHeritabilityIndividualInstitutesKnowledgeLinkMalignant NeoplasmsMalignant neoplasm of brainMeasurementMeasuresMentorshipMethodsMethylationMicrosatellite RepeatsModelingMutationPatient CarePatientsPatternProductionProtocols documentationRNARecordsResearchResearch PersonnelResearch ProposalsResistanceSamplingScientistSeveritiesSomatic MutationStructureSystemTechnologyTestingTimeTrainingTumor stageWorkaccurate diagnosisaggressive therapyanticancer researchbasecancer cellcancer therapycareercareer developmentclinical caredesigndiagnostic biomarkerdriver mutationeffective therapyepigenetic markerepigenomegenetic makeupgenome-wideimprovedinnovationinsightlongitudinal datasetmultiple data typesmultiple omicsmutantnovelpersonalized chemotherapyresponsesingle cell sequencingsingle cell technologysingle-cell RNA sequencingtargeted treatmenttherapeutic targettooltranscriptometranscriptomicstreatment responsetumortumor DNAtumor progression
项目摘要
PROJECT SUMMARY / ABSTRACT
Research Plan: Tumor evolution is a fundamental obstacle to cancer treatment, as malignant cells adapt to
treatment and change during progression. Understanding these adaptations is key to not only identifying
vulnerable gene targets, but also intervening during the optimal time window, before the targets become
obsolete. Charting this evolution requires understanding the genetic and epigenetic events that drive or
accompany disease progression, but these are largely unmapped in many malignancies. A case in point is diffuse
glioma, an incurable brain cancer composed of distinct cellular states that dramatically change in relative
abundance during glioma progression, ultimately changing the response to treatment. Efforts to decode glioma
evolution have been limited: while we have characterized the distinct glioma cell states, we have not found their
genetic and epigenetic drivers or measured how these affect cell states abundance throughout progression. To
this end, we have developed novel single-cell technologies to concurrently profile in the same cell i) the
transcriptome and epigenome (specifically, DNA methylation) and ii) the transcriptome and genome (DNA
mutations) at an unprecedented detection rate.
First, by combining genotype with cellular state data, I will define how somatic mutations dysregulate
transcriptional patterns, resulting in cellular states (Aim 1a), and characterize how somatic mutations dictate
glioma lineage structure (Aim 1b). By combining this with my postdoctoral work – characterizing how epigenetic
diversification contributes to transcriptomic diversity – I will create the first multi-dimensional model of glioma
evolution. Second, I will use our method to measure single-cell DNA methylation and transcriptional profiles in
samples taken longitudinally from the same patients. This will test the hypothesis that dysregulated epigenetic
patterns contribute to glioma progression, and it will not only provide a multi-dimensional model of glioma
progression, but will also provide epigenetic markers to track progression in the clinic (Aim 2). Finally, I will
improve diagnosis in the clinical setting by designing a tool that infers cell state composition, progression and
likely response to treatment based on data from the bulk DNA methylation assay that is routinely done in the
clinic (Aim 3). These studies will pave the way towards novel glioma treatments, accurate diagnoses and optimal
timing of treatment.
Career Development Plan: I have outlined a 5-year career development plan to meet my goal of becoming an
independent investigator in cancer biology who focuses on intrinsic determinants of tumor progression and
response to treatment. I have assembled a Mentorship Committee of leaders in the field, with whom I will train
to close remaining knowledge gaps in multi-omics evolution and how to leverage my results to support clinical
care. Finally, the Broad Institute constitutes the ideal environment for attaining my scientific and career goals,
given their outstanding research communities and track records of training independent scientists.
项目摘要/摘要
研究计划:肿瘤进化是癌症治疗的根本障碍,因为恶性细胞适应
进展过程中的治疗和变化。理解这些适应不仅是识别
脆弱的基因靶标,但也在最佳时间窗口内进行干预,在靶标成为
已经过时了。绘制这种进化的图表需要了解驱动或
伴随着疾病的进展,但这些在许多恶性肿瘤中很大程度上是没有映射的。一个很好的例子就是漫反射
胶质瘤,一种无法治愈的脑癌,由不同的细胞状态组成,亲属的
在胶质瘤进展过程中的丰富,最终改变对治疗的反应。破译胶质瘤的努力
进化是有限的:虽然我们已经描述了不同的胶质瘤细胞状态,但我们还没有发现它们
遗传和表观遗传驱动因素或测量这些因素如何在整个过程中影响细胞状态的丰度。至
为此,我们开发了新的单细胞技术,以便在同一细胞中同时分析i)
转录组和表观基因组(特别是DNA甲基化)和ii)转录组和基因组(DNA
突变)以前所未有的检测率。
首先,通过结合基因分型和细胞状态数据,我将定义体细胞突变是如何失调的
转录模式,导致细胞状态(目标1a),并表征体细胞突变如何决定
胶质瘤谱系结构(目标1b)。通过将这一点与我的博士后工作相结合--描述了表观遗传学
多样化有助于转录多样性-我将创建首个胶质瘤多维模型
进化论。其次,我将使用我们的方法来测量单细胞DNA甲基化和转录图谱
从相同的病人身上纵向采集的样本。这将检验这样一种假设,即失调的表观遗传
模式有助于胶质瘤的进展,它不仅将提供胶质瘤的多维模型
此外,还将提供表观遗传学标记,以跟踪临床进展情况(目标2)。最后,我会
通过设计一种工具来推断细胞状态的组成、进展和
可能对治疗的反应基于大量DNA甲基化测试的数据,这是常规的
诊所(目标3)。这些研究将为新的胶质瘤治疗方法、准确的诊断和优化铺平道路。
治疗时机。
职业发展计划:我概述了一个5年的职业发展计划,以实现我成为一名
癌症生物学独立研究员,专注于肿瘤进展的内在决定因素和
对治疗的反应。我已经组建了一个由该领域领导人组成的指导委员会,我将与他们一起进行培训
弥合多组学进化中剩余的知识差距,以及如何利用我的结果支持临床
关心。最后,博大学院是实现我的科学和职业目标的理想环境,
鉴于他们杰出的研究社区和培训独立科学家的记录。
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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Dana Silverbush其他文献
Dana Silverbush的其他文献
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{{ truncateString('Dana Silverbush', 18)}}的其他基金
Decoding glioma evolution and progression by multi-dimensional single-cell profiling
通过多维单细胞分析解码神经胶质瘤的进化和进展
- 批准号:
10461160 - 财政年份:2021
- 资助金额:
$ 13.04万 - 项目类别:
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