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

• 批准号: 10657973
• 负责人: Lam Cheung Tsoi
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10657973
• 关键词: ATAC-seq; Affect; African American population; African ancestry; Alleles; American; Biological; Biological Assay; Biological Markers; Bromouridine sequencing; CRISPR/Cas technology; Cells; Chromatin; Chromosome Mapping; Chronic; Clinical; Complex; Data; Development; Direct Costs; Disease; Disease model; Epigenetic Process; Ethnic Origin; Etiology; European; Facilities and Administrative Costs; Functional disorder; Gene Frequency; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Haplotypes; Heterogeneity; Heterozygote; Hi-C; IL17 gene; Immune; Immune System Diseases; Immune signaling; Individual; Inflammation; Inflammatory; Inflammatory Response; Machine Learning; Maps; Mediating; Mediator; Mission; Modeling; Molecular; Multiomic Data; Nucleic Acid Regulatory Sequences; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Play; Population; Population Heterogeneity; Predisposition; Prevalence; Psoriasis; Public Health; Quantitative Trait Loci; Regulation; Research; Resolution; Resources; Role; Shapes; Signal Transduction; Skin; Susceptibility Gene; TNF gene; United States National Institutes of Health; Variant; Work; causal variant; cohort; comorbidity; cost; cytokine; design; disease disparity; disease heterogeneity; functional genomics; genetic architecture; genetic variant; genome wide association study; genomic data; high risk; high throughput technology; human disease; improved; inflammatory modulation; innovation; inter-individual variation; interleukin-23; keratinocyte; multi-ethnic; multimodality; multiple omics; precision medicine; predict clinical outcome; promoter; response; skin disorder; transcriptome; transcriptomics

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。