Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
基本信息
- 批准号:10261987
- 负责人:
- 金额:$ 139.17万
- 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:2021-07-19 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAllergic DiseaseAllergic rhinitisAsthmaBacterial Artificial ChromosomesBiologicalBiologyBirthCategoriesCell physiologyCellsChildChronic DiseaseClinicalDataDevelopmentDiagnosisDiseaseEngineeringEnhancersEnvironmentEnvironmental ExposureEpithelialEpithelial CellsEthnic groupFood HypersensitivityGenesGeneticGenetic RiskGenomicsGoalsHealth Care CostsHealthcare SystemsHeritabilityHumanHypersensitivityImmuneImmunologicsImmunologyIndividualInfrastructureKnowledgeLinkLungLymphocyteMapsMolecularMyeloid CellsOutcomePathogenesisPeripheralPhenotypeProcessQuantitative Trait LociReportingResearch PersonnelResourcesRestRiskRoleServicesSmooth MuscleSpecificityTechnologyTestingTherapeuticTissuesTranslationsVariantWorkbiobankbronchial epitheliumcausal variantcell typeclinical heterogeneityclinical phenotypecohortcostdata managementdisease heterogeneitydisorder riskethnic diversitygene discoverygene functiongenome wide association studygenome-widemouse modelmulti-ethnicnew therapeutic targetnovelpersonalized medicineprecision medicineprogramsrespiratory smooth musclerisk variantskin hypersensitivitytherapeutic targettooltraittranscriptome sequencing
项目摘要
ABSTRACT
Asthma and allergic diseases are among the most common chronic diseases in children and adults, costing
our health care system over $80 billion per year. Rates have been increasing over the past 40 years and
therapeutic advances have been incremental. Over 150 loci have been reported in large genome-wide
association studies (GWAS) of asthma and allergic diseases, but their individual effects are small and these
variants account a small fraction of the overall genetic risk. Moreover, remarkably few of the GWAS findings for
asthma and allergic diseases have led to discoveries of causal variants or causal genes that contribute to
asthma and allergic disease pathogenesis. The latter has been particularly challenging due in part to the
significant clinical heterogeneity of these diseases, and in part to the lag in the development of powerful
statistical, molecular, and immunologic tools for bridging the trajectory from GWAS to gene discovery to
biology to translation. In this application, we propose a robust and comprehensive strategy for identifying
candidate causal variants and their target genes at asthma and allergic disease-associated loci, and for
characterizing (i) their functional effects in asthma and allergic disease-relevant cells types, including bronchial
epithelial cells, airway smooth muscle and lung immune cells, as well as peripheral immune cells, all in resting
and activated states; (ii) their downstream phenotypic effects on both broad categories of disease groups and
traits in the UK Biobank resource and on specific asthma and allergic disease endotypes in deeply phenotyped
ethnically-diverse subjects participating in asthma birth cohorts; and (iii) their immunologic effects in resting
and activated lung lymphocytes and myeloid cells and in “humanized locus” BAC-engineered mouse models.
These goals will be accomplished through a highly collaborative and synergistic program that includes two
projects, a service core, and an administrative core that together will that bridge the trajectory from GWAS to
translation through highly integrated studies by an exceptional team of investigators with expertise in genetics,
(epi)genomics, statistical genetics, and immunology. Achieving these goals will ultimately identify novel drug
targets and the individuals most likely to respond, providing a framework for precision medicine and
personalized treatment of asthma and allergic diseases.
摘要
哮喘和过敏性疾病是儿童和成人最常见的慢性疾病之一,费用高昂
我们的医疗保健系统每年超过800亿美元。在过去的40年里,
治疗进展是渐进的。据报道,在大基因组范围内,
哮喘和过敏性疾病的关联研究(GWAS),但它们的个体效应很小,
变异只占整体遗传风险的一小部分。此外,GWAS的研究结果中,
哮喘和过敏性疾病导致了致病变异或致病基因的发现,
哮喘和过敏性疾病的发病机制。后者特别具有挑战性,部分原因是
这些疾病的显著临床异质性,部分原因是强大的
统计,分子和免疫学工具,用于桥接从GWAS到基因发现的轨迹,
生物学翻译在这个应用程序中,我们提出了一个强大的和全面的战略,
哮喘和过敏性疾病相关基因座的候选致病变异体及其靶基因,以及
表征(i)它们在哮喘和过敏性疾病相关细胞类型中的功能作用,
上皮细胞、气道平滑肌和肺免疫细胞,以及外周免疫细胞,都处于静息状态,
和激活状态;(ii)它们对两大类疾病组的下游表型效应,
英国生物库资源中的特征以及深度表型分析中特定哮喘和过敏性疾病的内在型
参与哮喘出生队列的不同种族受试者;(iii)他们在静息状态下的免疫学效应
和活化的肺淋巴细胞和骨髓细胞以及“人源化基因座”BAC工程小鼠模型。
这些目标将通过一个高度协作和协同的计划来实现,该计划包括两个
项目、服务核心和管理核心,它们将共同连接从GWAS到
通过具有遗传学专业知识的杰出研究人员团队的高度综合研究进行翻译,
(EPI)基因组学、统计遗传学和免疫学。实现这些目标将最终确定新药
目标和个人最有可能作出反应,为精准医疗提供了一个框架,
哮喘和过敏性疾病的个性化治疗。
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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Marcelo A. Nobrega其他文献
Upregulation of emSYNGAP1/em expression in mice and human neurons by redirecting alternative splicing
通过重定向可变剪接来上调小鼠和人类神经元中 emSYNGAP1/em 的表达
- DOI:
10.1016/j.neuron.2023.02.021 - 发表时间:
2023-05-17 - 期刊:
- 影响因子:15.000
- 作者:
Runwei Yang;Xinran Feng;Alejandra Arias-Cavieres;Robin M. Mitchell;Ashleigh Polo;Kaining Hu;Rong Zhong;Cai Qi;Rachel S. Zhang;Nathaniel Westneat;Cristabel A. Portillo;Marcelo A. Nobrega;Christian Hansel;Alfredo J. Garcia III;Xiaochang Zhang - 通讯作者:
Xiaochang Zhang
Enhancers: five essential questions
增强子:五个关键问题
- DOI:
10.1038/nrg3458 - 发表时间:
2013-03-18 - 期刊:
- 影响因子:52.000
- 作者:
Len A. Pennacchio;Wendy Bickmore;Ann Dean;Marcelo A. Nobrega;Gill Bejerano - 通讯作者:
Gill Bejerano
Upregulation of emSYNGAP1/em expression in mice and human neurons by redirecting alternative splicing
通过重定向可变剪接来上调小鼠和人类神经元中 emSYNGAP1/em 的表达
- DOI:
10.1016/j.neuron.2023.02.021 - 发表时间:
2023-05-17 - 期刊:
- 影响因子:15.000
- 作者:
Runwei Yang;Xinran Feng;Alejandra Arias-Cavieres;Robin M. Mitchell;Ashleigh Polo;Kaining Hu;Rong Zhong;Cai Qi;Rachel S. Zhang;Nathaniel Westneat;Cristabel A. Portillo;Marcelo A. Nobrega;Christian Hansel;Alfredo J. Garcia III;Xiaochang Zhang - 通讯作者:
Xiaochang Zhang
Comparative genomics at the vertebrate extremes
脊椎动物极端情况下的比较基因组学
- DOI:
10.1038/nrg1350 - 发表时间:
2004-06-01 - 期刊:
- 影响因子:52.000
- 作者:
Dario Boffelli;Marcelo A. Nobrega;Edward M. Rubin - 通讯作者:
Edward M. Rubin
Marcelo A. Nobrega的其他文献
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{{ truncateString('Marcelo A. Nobrega', 18)}}的其他基金
Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
- 批准号:
10453773 - 财政年份:2021
- 资助金额:
$ 139.17万 - 项目类别:
Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
- 批准号:
10615778 - 财政年份:2021
- 资助金额:
$ 139.17万 - 项目类别:
Functional Genomics of IL-33 expression and asthma risk
IL-33 表达和哮喘风险的功能基因组学
- 批准号:
9247245 - 财政年份:2014
- 资助金额:
$ 139.17万 - 项目类别:
Functional Genomics of IL-33 expression and asthma risk
IL-33 表达和哮喘风险的功能基因组学
- 批准号:
8721683 - 财政年份:2014
- 资助金额:
$ 139.17万 - 项目类别:
Functional Genomics of IL-33 Expression and Asthma Risk
IL-33 表达和哮喘风险的功能基因组学
- 批准号:
9281175 - 财政年份:2014
- 资助金额:
$ 139.17万 - 项目类别:
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