Integrative and trans-ethnic study to understand psoriasis associated signals
了解银屑病相关信号的综合和跨种族研究
基本信息
- 批准号:10657973
- 负责人:
- 金额:$ 37.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAffectAfrican American populationAfrican ancestryAllelesAmericanBiologicalBiological AssayBiological MarkersBromouridine sequencingCRISPR/Cas technologyCellsChromatinChromosome MappingChronicClinicalComplexDataDevelopmentDirect CostsDiseaseDisease modelEpigenetic ProcessEthnic OriginEtiologyEuropeanFacilities and Administrative CostsFunctional disorderGene FrequencyGeneticGenetic ModelsGenetic TranscriptionGenetic VariationGenetic studyGenomicsGenotypeGoalsHaplotypesHeterogeneityHeterozygoteHi-CIL17 geneImmuneImmune System DiseasesImmune signalingIndividualInflammationInflammatoryInflammatory ResponseMachine LearningMapsMediatingMediatorMissionModelingMolecularMultiomic DataNucleic Acid Regulatory SequencesOutcomePathogenesisPathogenicityPathologicPathologyPathway interactionsPatient-Focused OutcomesPatientsPersonsPharmaceutical PreparationsPlayPopulationPopulation HeterogeneityPredispositionPrevalencePsoriasisPublic HealthQuantitative Trait LociRegulationResearchResolutionResourcesRoleShapesSignal TransductionSkinSusceptibility GeneTNF geneUnited States National Institutes of HealthVariantWorkcausal variantcohortcomorbiditycostcytokinedesigndisease disparitydisease heterogeneityfunctional genomicsgenetic architecturegenetic variantgenome wide association studygenomic datahigh riskhigh throughput technologyhuman diseaseimprovedinflammatory modulationinnovationinter-individual variationinterleukin-23keratinocytemulti-ethnicmultimodalitymultiple omicsprecision medicinepredict clinical outcomepromoterresponseskin disordertranscriptometranscriptomics
项目摘要
PROJECT SUMMARY
Psoriasis is a chronic immune-mediated skin disease that has a significant impact on public health, with annual
direct and indirect costs over $75 billion dollars in the US. Advancements in high throughput technology have
enabled the identification of genetic and genomic components in the Th17/IL-23 and NF𝜅B axes, associated
with psoriasis pathology. Although >80 psoriasis susceptibility regions have been revealed, considerable
challenges remain in narrowing down the causal genetic variations and discerning their pathological mechanisms
that shape disease etiology. Similarly, while NF𝜅B signaling is involved in psoriasis and different skin immune
disorders, we have very limited understanding of the mechanistic role genetic variants play in NF𝜅B regulation.
With the new extended psoriasis GWAS emerging, psoriasis can serve as an ideal skin disease model to study
this phenomenon in keratinocytes. Psoriasis has a prevalence rate of 1.3% among African Americans (AA),
however most US-established genomics studies of psoriasis have been conducted on European American (EA)
populations. Our preliminary data show that the fine-mapping of components can be facilitated by integrating
genetic, epigenetic, and genomic information in a multi-ethnic analysis design, especially when including
individuals with African ancestry. We have illustrated elevated NF𝜅B signaling response in keratinocytes among
AA individuals and that inter-individual variations in inflammatory signature can have significant clinical
implications for the assessment of drug response. The long-term goal of this project is to identify biological
mechanisms for disease heterogeneity among psoriatic patients, and our overall objective is to utilize a trans-
ethnic design to advance the identification of psoriasis-associated regulatory mechanisms involved in the
modulation of NF𝜅B signaling in keratinocytes. We will apply an integrative approach to study multi-omics data
and leverage trans-ethnic information to fine-map the genetic/genomic components associated with inter-
individual inflammatory responses, providing a model to understand disease disparity among psoriatic patients
of different ethnicities. We will i) fine-map the response expression quantitative trait loci (reQTLs) modulating
NF𝜅B and other inflammatory signaling in keratinocytes; ii) determine regulatory mechanisms of psoriasis signal
that drive NF𝜅B signaling in keratinocytes at the cellular level using multi-modal genomic data; iii) utilize genetic
and genomic components participating in NF𝜅B signaling, to model clinical presentations and outcomes for
patients from an ongoing longitudinal psoriasis cohort. Successful completion of the project will have an
important positive impact by providing enhanced resolution and power to identify determinants of inter-individual
variations in inflammatory responses.
项目摘要
银屑病是一种慢性免疫介导的皮肤病,对公众健康有重大影响,每年
直接和间接成本超过750亿美元。高通量技术的进步
能够鉴定Th 17/IL-23和NFκ B B轴中的遗传和基因组成分,
牛皮癣的病理学虽然已经揭示了>80个银屑病易感区域,但相当多的银屑病易感区域已经被发现。
在缩小致病基因变异和辨别其病理机制方面仍然存在挑战
形成疾病的病因学。同样,虽然NFκ B B信号通路参与银屑病和不同的皮肤免疫反应,
虽然我们对NFκ B B调节的机制作用的了解非常有限。
随着新的扩展型银屑病GWAS的出现,银屑病可以作为一种理想的皮肤病模型进行研究
角质形成细胞中的这种现象。银屑病在非裔美国人(AA)中的患病率为1.3%,
然而,大多数美国建立的银屑病基因组学研究都是在欧洲美国人(EA)中进行的。
人口。我们的初步数据表明,组件的精细映射可以通过集成来促进
多种族分析设计中的遗传、表观遗传和基因组信息,特别是当包括
有非洲血统的人。我们已经阐明了在角质形成细胞中NFκ B B信号应答的升高,
AA个体中的炎症特征的个体间差异可以具有显著的临床意义。
对药物反应评估的影响。该项目的长期目标是确定生物
银屑病患者疾病异质性的机制,我们的总体目标是利用一个反式
种族设计,以促进银屑病相关的调节机制,
角质形成细胞中NFκ B B信号传导的调节。我们将采用综合的方法来研究多组学数据
并利用跨种族信息来精细绘制与跨种族相关的遗传/基因组成分,
个体炎症反应,为了解银屑病患者之间的疾病差异提供了模型
不同的种族。我们将i)精细定位响应表达数量性状基因座(reQTLs),
角质形成细胞中NFκ B B和其他炎症信号传导; ii)确定银屑病信号的调节机制
其使用多模态基因组数据在细胞水平上驱动角质形成细胞中的NFκ B B信号传导; iii)利用遗传
和参与NFκ B B信号传导的基因组成分,以模拟
来自正在进行的纵向银屑病队列的患者。项目的成功完成将使
通过提供更高的分辨率和能力来确定个体间的决定因素,
炎症反应的变化。
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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Lam Cheung Tsoi其他文献
Lam Cheung Tsoi的其他文献
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{{ truncateString('Lam Cheung Tsoi', 18)}}的其他基金
Integrative Biology Approach to Identify and Characterize Roles of lncRNAs Associated with Psoriasis Pathology
识别和表征与银屑病病理学相关的 lncRNA 作用的综合生物学方法
- 批准号:
9371181 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
Integrative Biology Approach to Identify and Characterize Roles of lncRNAs Associated with Psoriasis Pathology
识别和表征与银屑病病理学相关的 lncRNA 作用的综合生物学方法
- 批准号:
9761992 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
Integrative Biology Approach to Identify and Characterize Roles of lncRNAs Associated with Psoriasis Pathology
识别和表征与银屑病病理学相关的 lncRNA 作用的综合生物学方法
- 批准号:
10246892 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
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