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 牛皮癣是一种慢性免疫介导的皮肤病，对公共卫生有重大影响，年度 在美国，直接和间接的成本超过750亿美元。高通量技术的进步已经 能够鉴定TH17/IL-23和NF𝜅B轴中遗传和基因组成分 牛皮癣病理学。尽管已经揭示了80个牛皮癣易感性区域，但很大 挑战在缩小因果遗传变异并辨别其病理机制方面仍然存在挑战 那种疾病病因。同样，虽然NF𝜅B信号传导涉及牛皮癣和不同的皮肤免疫 疾病，我们对NF𝜅B调节中遗传变异的机理作用的理解非常有限。 随着新的牛皮癣的新出现，牛皮癣可以作为研究理想的皮肤病模型 这种现象在角质形成细胞中。牛皮癣的患病率在非洲裔美国人（AA）中为1.3％， 但是，大多数美国建立的牛皮癣基因组学研究是对欧美（EA）进行的 人群。我们的初步数据表明，可以通过集成来准备组件的精细映射 多种族分析设计中的遗传，表观遗传学和基因组信息，尤其是在包括 非洲血统的人。我们已经说明了角质形成细胞中的NF𝜅B信号响应的升高 AA个体以及炎症特征的个体间变化可以具有明显的临床 对药物反应评估的影响。该项目的长期目标是确定生物学 银屑病患者疾病异质性的机制，我们的总体目标是利用跨 种族设计以促进鉴定牛皮癣相关的调节机制 调节角质形成细胞中NF𝜅B信号传导的调节。我们将采用综合方法来研究多摩斯数据 并利用跨种族信息来对与间隔相关的遗传/基因组成分进行绘制 个体炎症反应，提供了一个模型来了解银屑病患者的疾病差异 不同的种族。我们将仔细绘制响应表达式定量性状基因座（REQTLS）调制 角质形成细胞中的NF𝜅B和其他炎症信号传导； ii）确定牛皮癣信号的调节机制 使用多模式基因组数据，在细胞水平的角质形成细胞中驱动NF𝜅B信号传导； iii）使用通用 以及参与NF𝜅B信号传导的基因组成分，以建模临床表现和结果 来自正在进行的纵向牛皮癣队列的患者。成功完成项目将有一个 通过提供增强的分辨率和能力来识别个体间的确定词，重要的积极影响 炎症反应的变化。