Mechanisms of New-Onset Autoimmunity/Longitudinal Immune Systems Analysis (MONA-LISA)

新发自身免疫/纵向免疫系统分析（MONA-LISA）的机制

• 批准号: 10655219
• 负责人: Joel Marvin Guthridge
• 金额: $ 129.11万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655219
• 关键词: Antimalarials; Antinuclear Antibodies; Atlases; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Lymphocytes; Biological Markers; Black Populations; Blinded; Blood specimen; Categories; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Classification; Clinical; Clinical Data; Clinical Trials; Clinical assessments; Cutaneous Involvement; DNA; Data; Data Set; Development; Diagnosis; Disease; Double-Blind Method; Down-Regulation; Enrollment; Epidemiology; Epigenetic Process; Ethnic Population; Expression Profiling; Gene Expression Regulation; Genetic Polymorphism; Genomics; Goals; Health Personnel; Health Transition; Hydroxychloroquine; Immune response; Immune system; Immunologics; Immunophenotyping; Individual; Intention; Intervention Trial; Investments; Knowledge; Laboratories; Learning; Lipids; Lupus; Lupus Erythematosus; Measurement; Mediating; Mediator; Messenger RNA; Metabolic; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Not Hispanic or Latino; Observational Study; Organ; Participant; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patients; Performance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Placebo Control; Plasma; Population; Populations at Risk; Portraits; Prevention; Proteomics; Protocols documentation; RNA; Randomized; Recording of previous events; Research Personnel; Resources; Risk; Risk Assessment; Role; Serology; Serum; Specimen; Standardization; Systemic Lupus Erythematosus; Systems Analysis; T-Lymphocyte; Testing; United States National Institutes of Health; Urine; Variant; Work; cell type; chemokine; clinical phenotype; cohort; cytokine; diagnostic tool; disability; disorder prevention; effective intervention; epigenomic profiling; epigenomics; high dimensionality; immunoregulation; lipidomics; mRNA Expression; metabolomics; multiple omics; new therapeutic target; novel; novel therapeutics; peripheral blood; phase 2 study; prevent; primary endpoint; prognostic tool; recruit; response; risk variant; screening; single-cell RNA sequencing; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT The Mechanisms of New-Onset Autoimmunity-Longitudinal Immune Systems Analysis (MONA-LISA) will use clinical data and biospecimens obtained during performance of the clinical trial, Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE, NCT03030118) to investigate immunological mechanisms that propel individuals who have asymptomatic or minimally symptomatic autoimmunity towards a definite diagnosis of systemic lupus erythematosus. These data and specimens are a unique resource, representing longitudinal clinical assessments, patient-reported outcomes, DNA, RNA, serum, plasma, peripheral blood mononuclear cells and urine obtained in a standardized manner before, during, and after the progression from Incomplete Lupus Erythematosus to Systemic Lupus Erythematosus (SLE) – an observation that occurred in twenty percent of the SMILE participants available for study. The overall objective of the study is to learn the underlying immunological, genomic, and metabolic differences present in individuals who progress to SLE compared to those that do not progress with goals to both develop better diagnostic and prognostic tools for health care providers as well as describe novel therapeutic targets so that individuals with early features of autoimmunity can be prevented from progressing to a state of organ damage and disability. The Specific Aims of MONA-LISA include: 1) Obtain a comprehensive, multiplex analysis of the peripheral blood immunophenotype of progressors and non-progressors in the SMILE cohort using a novel 137-plex CITE-seq analysis, sn-ATAC-seq, sc-RNA-seq and T and B cell repertoire determination to create a robust, quantitative atlas of cell-specific mRNA and epigenomic profiling in PBMC of these individuals. 2) Perform targeted genomic sequencing to categorize regulatory and structural variants of SLE risk loci to tie together the transcriptomic and epigenomic data and create novel risk assessments based on gene regulation. 3) Explore plasma and serum metabolic and lipid components that can serve as novel features that classify the risk of SMILE participants who progress towards classification with lupus. 4) Lastly, because SMILE enrolled fewer Black individuals than are represented in the epidemiology of prevalent lupus patients, we will perform a focused recruitment of non-European individuals with ILE and compare their multi-omic characterization of immunophenotypes described in Aims 1-3. This will allow more complete and generalizable conclusions to be drawn across ethnic groups and identify any ancestry-specific variations in the risk of autoimmunity progression that can explain the observed differences in lupus epidemiology. When completed, MONA-LISA will provide researchers and health care providers with better tools to predict who will develop lupus and create more effective interventional trials for disease prevention.

项目摘要/摘要 新发育自身免疫性 - 垂直免疫系统分析（MONA-LISA）的机制将使用 在临床试验的性能中获得的临床数据和生物测量，对抗疟疾的研究 不完整的红斑狼疮（微笑，NCT03030118）研究免疫机制 推动具有渐近或最小症状自身免疫性的个体朝着定义的诊断 全身性红斑狼疮。这些数据和标本是一个独特的资源，代表纵向 临床评估，患者报告的结果，DNA，RNA，血清，血浆，外周血单核 细胞和尿液在不完整的过程中，期间和之后以标准化的方式获得 狼疮红膜到系统性红斑狼疮（SLE） - 二十次发生的观察结果 可以学习的微笑参与者的百分比。该研究的总体目的是学习 发展到SLE的个体中存在的基本免疫，基因组和代谢差异 与那些不进步的目标相比，既可以开发更好的诊断和预后工具 医疗保健提供者以及描述新颖的治疗靶标，以便具有早期特征的个人 可以防止自身免疫发展到器官损伤和残疾状态。 Mona-Lisa的具体目的包括：1）获得周围的全面多重分析 使用小说137-plex，在微笑队列中的进度者和非培训者的血液免疫表型 CITE-SEQ分析，SN-ATAC-SEQ，SC-RNA-SEQ和T和B细胞库库的确定，以创建强大的， 这些个体的PBMC中细胞特异性mRNA和表观基因组分析的定量地图集。 2）执行 靶向基因组测序与SLE风险基因座的类别调节和结构变体，以将 转录组和表观基因组数据，并根据基因调节创建新的风险评估。 3）探索 血浆和血清代谢和脂质成分，可以用作新的特征，这些特征可以归类 微笑的参与者朝着与狼疮分类进行分类的参与者。 4）最后，因为微笑少了 黑人个体比普遍的狼疮患者的流行病学所代表的，我们将执行 专注于具有ILE的非欧洲个体的招募，并比较其多摩尼克的表征 AIMS 1-3中描述的免疫表型。这将允许更完整且可概括的结论是 跨种族吸引并确定自身免疫风险的任何特定于祖先的变化 可以解释狼疮流行病学差异的进展。完成后，Mona-Lisa 将为研究人员和医疗保健提供者提供更好的工具，以预测谁将开发狼疮并创建 预防疾病的更有效的介入试验。