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.

项目概要 牛皮癣是一种慢性免疫介导的皮肤病，对公众健康具有重大影响，每年都会发生 美国的直接和间接成本超过 750 亿美元。高通量技术的进步 能够识别 Th17/IL-23 和 NF𝜅B 轴中的遗传和基因组成分，相关 与牛皮癣病理。尽管已揭示超过 80 个银屑病易感区域，但仍有相当多的 在缩小因果遗传变异范围并辨别其病理机制方面仍然存在挑战 形成疾病病因学。同样，虽然 NF𝜅B 信号传导参与牛皮癣和不同的皮肤免疫 对于遗传变异在 NF𝜅B 调节中发挥的机制作用，我们的了解非常有限。 随着新的扩展银屑病 GWAS 的出现，银屑病可以作为研究理想的皮肤病模型 角质形成细胞中存在这种现象。非裔美国人 (AA) 中银屑病的患病率为 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裔美国人 (EA) 身上进行的 人口。我们的初步数据表明，通过集成可以促进组件的精细映射 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 具有非洲血统的人。我们已经证明角质形成细胞中 NF𝜅B 信号反应升高 AA 个体以及炎症特征的个体间差异可能具有显着的临床意义 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反式 种族设计以促进银屑病相关调节机制的识别 角质形成细胞中 NF𝜅B 信号传导的调节。我们将应用综合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，提供一个模型来了解银屑病患者之间的疾病差异 不同种族的。我们将 i) 精细绘制响应表达数量性状位点 (reQTL) 调节 角质形成细胞中的 NF𝜅B 和其他炎症信号传导； ii) 确定银屑病信号的调节机制 使用多模式基因组数据在细胞水平上驱动角质形成细胞中的 NF𝜅B 信号传导； iii) 利用遗传 和参与 NF𝜅B 信号传导的基因组成分，以模拟临床表现和结果 来自正在进行的纵向银屑病队列的患者。该项目的成功完成将带来 通过提供增强的分辨率和能力来确定个体间的决定因素，从而产生重要的积极影响 炎症反应的变化。