The Functional Consequences of the 17q12 Asthma Susceptibility Locus
17q12 哮喘易感基因座的功能后果
基本信息
- 批准号:9113682
- 负责人:
- 金额:$ 84.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:17q12AlbuterolAllergensAsthmaBinding ProteinsBronchodilator AgentsCD4 Positive T LymphocytesCell physiologyCellsChemosensitizationChromosomesDataDevelopmentDiseaseEnzymesEpithelialEpithelial CellsEthnic OriginExtrinsic asthmaFoundationsGene ExpressionGenesGeneticGenotypeGlucosylceramidesHaplotypesHealthHumanIn VitroIndividualInflammatoryKnowledgeLiquid substanceLungMeasuresMediatingMediator of activation proteinMetabolicMetabolismMolecularMusPathogenesisPhysiologicalPlasmaPredispositionProductionResolutionRiskSamplingSerineSeverity of illnessSphingolipidsSusceptibility GeneTestingTimeTransferaseTransgenic MiceTransgenic OrganismsUp-RegulationVariantZona Pellucidaairway hyperresponsivenessairway inflammationallergic airway inflammationasthmaticbronchial epitheliumcell typechromatin remodelingcytokinegenetic associationgenetic variantgenome wide association studyhuman datain vivoknock-downmethacholinemouse modelnoveloverexpressionpromoterresponse
项目摘要
DESCRIPTION (provided by applicant): The objective of this proposal is to identify the asthma gene that is responsible for the genetic associations on chromosome 17q12 with asthma. A common haplotype on chromosome 17q12 is the strongest, most consistently reproducible asthma-susceptibility locus to emerge from genome-wide association studies. The 17q12 asthma-risk haplotype confers regional chromatin remodeling of three neighboring genes: ORMDL3, GSDMB, and ZPBP2. However, from the available genetic data alone, it is impossible to conclude with any certainty which of these three is responsible for the genetic association. From our preliminary data, we observe that both ORDML3 and GSDMB are constitutively expressed in bronchial epithelium, and that their overexpression results in discrete
molecular and cellular consequences of importance in asthma. In contrast, we find that ZPBP2 is not expressed in either bronchial epithelium or other asthma-relevant cell types. We thus hypothesize that ORMDL3 or GSDMB, but not ZPBP2, confers asthma risk. To test this hypothesis, we propose three Specific Aims. In Specific Aim 1, we will study inducible transgenic mice generated in our lab that conditionally over express ORMDL3 or GSDMB in bronchial epithelium. We will assess the effects of each gene's over expression in an established murine model of allergic asthma, examining the physiological, histological, and metabolic consequences. In Specific Aim 2, we will experimentally assess (via in vitro knockdown and over expression studies) the independent cellular consequences of ORMDL3 and GSDMB expression in human bronchial epithelial cells derived from individuals homozygous for the risk and protective 17q12 haplotypes. In Specific Aim 3, we will study the relationship of 17q12 haplotype with sphingolipid metabolism in several ways (i) we will measure sphingolipid levels in the airways & lung homogenates from our murine studies in Aim 1 to determine the in vivo effects of ORMDL3 expression; (ii) we will examine by genetic association whether the functional 17q12 regulatory variant contributes to variations in plasma sphingolipid levels in 200 asthmatics; and (iii) we will correlate these plasma sphingolipid levels
with bronchodilator response to albuterol and airways hyperreactivity to methacholine. The knowledge gained through these proposed efforts will advance our understanding of this most important asthma-susceptibility locus, and will provide the requisite foundations for the development of novel asthma therapies.
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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Benjamin Alexander Raby其他文献
Benjamin Alexander Raby的其他文献
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{{ truncateString('Benjamin Alexander Raby', 18)}}的其他基金
Integrative Genomics of the Asthma-COPD Overlap
哮喘-慢性阻塞性肺病重叠的综合基因组学
- 批准号:
9982414 - 财政年份:2016
- 资助金额:
$ 84.58万 - 项目类别:
The Functional Consequences of the 17q12 Asthma Susceptibility Locus
17q12 哮喘易感基因座的功能后果
- 批准号:
8972420 - 财政年份:2015
- 资助金额:
$ 84.58万 - 项目类别:
Anti- IL5 therapy for Churg-Strauss Syndrome: a double blind randomized, placebo-
治疗 Churg-Strauss 综合征的抗 IL5 疗法:双盲、随机、安慰剂
- 批准号:
8012687 - 财政年份:2010
- 资助金额:
$ 84.58万 - 项目类别:
The Asthma BioRepository for Integrative Genomics Research
用于综合基因组学研究的哮喘生物存储库
- 批准号:
7939844 - 财政年份:2009
- 资助金额:
$ 84.58万 - 项目类别:
The Asthma BioRepository for Integrative Genomics Research
用于综合基因组学研究的哮喘生物存储库
- 批准号:
7853777 - 财政年份:2009
- 资助金额:
$ 84.58万 - 项目类别:
Genetics and Gene Expression Profiling in Asthma
哮喘的遗传学和基因表达谱
- 批准号:
7839331 - 财政年份:2009
- 资助金额:
$ 84.58万 - 项目类别:
Genetics and Gene Expression Profiling in Asthma
哮喘的遗传学和基因表达谱
- 批准号:
8586533 - 财政年份:2007
- 资助金额:
$ 84.58万 - 项目类别:
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