Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics
利用人类遗传学靶向不确定潜力的克隆造血
基本信息
- 批准号:10263942
- 负责人:
- 金额:$ 43.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAgeAgingBiologicalBiologyCardiovascular DiseasesCardiovascular systemChronic DiseaseClinical MedicineClonal ExpansionCommunitiesComputing MethodologiesDataDevelopmentDiseaseDisease OutcomeEnvironmental Risk FactorFundingGene ExpressionGenesGenetic VariationGenomeGenomicsGerm-Line MutationHematopoiesisHematopoietic NeoplasmsHematopoietic stem cellsHumanHuman CloningHuman GeneticsIL6 geneIn VitroIndividualInstitutesInterleukin-6Internal MedicineInterventionJAK2 geneLeadMalignant NeoplasmsMediatingMentorshipMethodsMinorityMutationMyocardial InfarctionNational Heart, Lung, and Blood InstitutePathway interactionsPatientsPopulationPositioning AttributePrecision therapeuticsPreventionResearchResidenciesResourcesRiskRisk FactorsSamplingSignal TransductionSomatic MutationTestingTherapeuticTimeTrainingTrans-Omics for Precision MedicineVariantWhole BloodWorkcancer riskcareercohortdisorder riskexperimental studyfollow-upgenetic approachgenetic associationgenome sequencinggenome wide association studyhuman genomicsinsightmortality riskmouse modelnovelpreventprogramssingle-cell RNA sequencingskillsstem cell functiontherapeutic targettranscriptome sequencing
项目摘要
Project Summary
Age is the dominant risk factor for most chronic diseases; yet mechanisms by which aging confers
risk are largely unknown. One unifying feature of aging diseases as diverse as cardiovascular
disease and cancer is the acquisition of somatic mutations in hematopoietic stem cells (frequently
DNMT3A, TET2, JAK2), termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). I will
leverage human genomics to identify pathways underlying CHIP acquisition, clonal expansion
and disease. Why only some individuals develop CHIP, why only some CHIP clones expand, and
why only a minority of CHIP carriers develop disease is presently unknown. I hypothesize that
germline genetic variation contributes to CHIP acquisition, clonal expansion and disease. I
propose to (1) identify CHIP in existing genome sequencing data and perform genetic association
analyses of CHIP in >800,000 individuals and evaluate how CHIP-associated variants alter
human hematopoietic stem cell function in in-vitro follow-up experiments. (2) Define the
determinants of CHIP clonal expansion and association with disease. (3) Identify gene expression
programs that cause clonal expansion and disease. Successful execution of these aims will
highlight therapeutic targets for the prevention of CHIP, clonal expansion and disease for which
no therapies currently exist. Such a CHIP therapeutic would potentially be an intervention for
multiple aging diseases. To succeed in these aims, I will receive significant institutional support
from MGH including funding, space, protected time and mentorship to establish my research
group. The Broad Institute will provide access to leading-edge genomic resources. I will leverage
my unique position at the interface of these two scientific communities to establish a leading
research program focused on CHIP. Having completed rigorous training in genomics,
cardiovascular biology, and clinical medicine, I am now poised to leverage these skills, resources
and mentorship to embark on my own independent research career without delay.
项目摘要
年龄是大多数慢性病的主要危险因素;然而,衰老的机制
风险在很大程度上是未知的。老年疾病的一个统一特征,如心血管疾病
疾病和癌症是在造血干细胞中获得体细胞突变(经常
DNMT3A、TET2、JAK2),称为不确定潜能克隆性造血(CHIP)。这就做
利用人类基因组学识别芯片获取、克隆扩张的潜在途径
和疾病。为什么只有一些人开发芯片,为什么只有一些芯片克隆扩大,以及
为什么只有少数芯片携带者会患上疾病,目前尚不清楚。我假设
生殖系遗传变异导致芯片获取、克隆性扩张和疾病。我
提出(1)识别现有基因组测序数据中的芯片并进行遗传关联
对80万名芯片携带者进行分析,并评估芯片相关变异的变化
体外随访实验中的人造血干细胞功能。(2)界定
芯片克隆性扩张的决定因素及其与疾病的关联。(3)鉴定基因表达
导致克隆扩张和疾病的程序。这些目标的成功实现将
突出预防CHIP、克隆性扩张和疾病的治疗靶点
目前还没有治疗方法。这样的芯片疗法可能是对
多种老年病。为了实现这些目标,我将得到重要的机构支持
来自麻省理工学院的资金、空间、保护时间和指导,以建立我的研究
一群人。博德研究所将提供访问尖端基因组资源的途径。我会利用
我的独特地位在这两个科学界的接口上建立了领先的
研究计划重点放在芯片上。在完成了严格的基因组学培训后,
心血管生物学和临床医学,我现在准备利用这些技能、资源
和导师立即开始我自己的独立研究生涯。
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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Alexander Bick的其他文献
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{{ truncateString('Alexander Bick', 18)}}的其他基金
Automation of Liquid Nitrogen Freezer for Cryopreservation of Unique Human Biospecimens at the Vanderbilt Biospecimen Storage Facility
在范德比尔特生物样本储存设施中使用液氮冷冻机自动化冷冻保存独特的人类生物样本
- 批准号:
10736276 - 财政年份:2023
- 资助金额:
$ 43.25万 - 项目类别:
Clonal hematopoiesis and inherited genetic variation in sickle cell disease
镰状细胞病的克隆造血和遗传变异
- 批准号:
10638404 - 财政年份:2023
- 资助金额:
$ 43.25万 - 项目类别:
Targeting Clonal Hematopoiesis of Indeterminate Potential Using Human Genetics
利用人类遗传学靶向不确定潜力的克隆造血
- 批准号:
10378932 - 财政年份:2021
- 资助金额:
$ 43.25万 - 项目类别:
Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics
利用人类遗传学靶向不确定潜力的克隆造血
- 批准号:
10016727 - 财政年份:2020
- 资助金额:
$ 43.25万 - 项目类别:
Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics
利用人类遗传学靶向不确定潜力的克隆造血
- 批准号:
10685925 - 财政年份:2020
- 资助金额:
$ 43.25万 - 项目类别:
Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics
利用人类遗传学靶向不确定潜力的克隆造血
- 批准号:
10480770 - 财政年份:2020
- 资助金额:
$ 43.25万 - 项目类别:
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