DNA methylation in the development of multiple sclerosis

DNA甲基化在多发性硬化症发展中的作用

• 批准号: 10660209
• 负责人: Jorge R. Oksenberg
• 金额: $ 65.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660209
• 关键词: 3-Dimensional; 6p21; Affect; African American; Age; Antibody Therapy; Atlases; Automobile Driving; B-Lymphocytes; Biological Markers; Blood; CD19 gene; California; Cell Communication; Cell physiology; Cell surface; Cells; Cellular Assay; Cerebrospinal Fluid; Chromatin; Chromosomes; Clinical; Coupled; DNA; DNA Methylation; Data; Data Set; Development; Diagnosis; Disease; Disease model; Disease susceptibility; Epigenetic Process; Event; Gene Expression; Genetic; Genotype; Goals; Heterogeneity; Immune; Immunologics; Individual; Ligands; Link; Magnetic Resonance Imaging; Major Histocompatibility Complex; Maps; Measurement; Measures; Modality; Modeling; Modification; Multiple Sclerosis; Participant; Pathogenesis; Pathologic; Patient Recruitments; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Process; Prognosis; Quantitative Trait Loci; Repression; Research; Resolution; Risk; Role; Sampling; Shapes; Susceptibility Gene; Symptoms; System; Therapeutic; Time; Update; Validation; Visualization; biobank; case control; cohort; disability; disorder risk; diverse data; epigenomics; follow-up; genome wide association study; histone modification; insight; multiple omics; multiple sclerosis patient; novel; phenotypic data; polygenic risk score; prognostic; programs; receptor; sex; single-cell RNA sequencing; statistics; tositumomab; transcriptome

Summary This application is concerned with the study of epigenetics events affecting multiple sclerosis (MS) risk and progression. We present preliminary results consistent with widespread differential hypomethylation in peripheral CD19+ B cells at the time of diagnosis, posing a mechanistic link to the clinical efficiency of anti-CD20 antibody treatment for this disease. We build on these results and access to informative and diverse data- and sample-sets to propose in Specific Aim 1 the simultaneous assessment of single-cell gene expression (scRNA-seq), chromatin accessibility (scATAC-seq), and cell surface markers in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells from treatment naïve MS patients at the time of clinical onset and well matched controls, and link in Aim 2 to the individuals’ DNA variance to develop global and cell-specific genetic burdens associated with disease expression. In Aim 3 we connect the emerging epigenetic and transcriptome signatures with cell function using the Beacon® system optofluidic platform to visualize and assess cellular phenotypes at the single-cell level. In Aim 4 we implement a targeted trimodal single-cell assay to describe the epigenetic landscape of the principal MS susceptibility locus, the Major Histocompatibility Complex in chromosome 6p21. By systematically integrating single cell chromatin states, DNA variance, and gene expression data, we expect to gain important novel information about pathogenesis. Moreover, we will identify cell-specific epigenetic signatures associated with MS clinical onset, potentially serving as biomarkers of affectation status. The meticulous clinical follow up of study participants offers an opportunity to assess their prognostic potential.

概括 该应用与影响多发性硬化症（MS）风险的表观遗传学事件的研究有关 和进展。我们提出的初步结果与宽度差分一致 诊断时外周CD19+ B细胞中的低甲基化，在机械上构成了与 该疾病的抗CD20抗体治疗的临床效率。我们以这些结果为基础 在特定目标中获取信息丰富和多样化的数据和样本集以简单目的访问提案 评估单细胞基因表达（SCRNA-SEQ），染色质可及性（SCATAC-SEQ）和 配对脑脊液（CSF）和外周血单核细胞中的细胞表面标记 在临床发作和匹配良好的对照时治疗幼稚的MS患者，AIM 2中的链接到 个体的DNA差异，以发展与全球和细胞特异性遗传伯nens相关 疾病表达。在AIM 3中，我们将新兴的表观遗传和转录组特征连接起来 使用BEACON®系统Optofluidic平台可视化和评估细胞表型的细胞功能 在单细胞级别。在AIM 4中，我们实现了一个有针对性的三型单细胞测定法来描述 主要MS敏感性基因座的表观遗传景观，这是主要的组织相容性复合物 6p21染色体。通过系统地整合单细胞染色质状态，DNA方差和基因 表达数据，我们希望获得有关发病机理的重要新信息。而且，我们会的 鉴定与MS临床发作相关的细胞特异性表观遗传学特征，有可能用作 情感状况的生物标志物。研究参与者的细致临床随访提供了 评估其预后潜力的机会。