Autoimmune Drivers and Protectors Team Science (ADAPTS)

自身免疫驱动器和保护器团队科学 (ADAPTS)

• 批准号: 10657232
• 负责人: JUDITH A JAMES
• 金额: $ 132.33万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657232
• 关键词: ATAC-seq; Address; Age; Apoptosis; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Avidity; B-Cell Activation; B-Lymphocytes; Benign; Bioinformatics; Biological Markers; Cell Count; Cells; Cellular Immunology; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Characteristics; Chronic; Classification; Clinical; Clinical Data; Collaborations; Collection; Data; Development; Disease; Disease Progression; Early Diagnosis; Epigenetic Process; Epitope spreading; Exhibits; Female of child bearing age; Flare; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genomics; Immune; Immune Targeting; Immunology; Impairment; Individual; Inflammatory; Innate Immune Response; Interferon Type I; Knowledge; Link; Lupus; Lymphopenia; Measures; Mediating; Mediator; Medical; Metabolic; Metabolism; Minority Groups; Mitochondria; Molecular; Morbidity - disease rate; Myeloid Cells; Natural History; Nucleic Acids; Onset of illness; Organ; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Population; Prevention; Prevention trial; Process; Production; Productivity; Proliferating; Publishing; Questionnaires; RNA; Regulation; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Risk Reduction; Role; Sampling; Science; Scientist; Sentinel; Signal Transduction; Source; Specificity; System; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Testing; Time; Tissues; Treatment-related toxicity; Validation; Viral; adaptive immune response; autoreactive T cell; biomarker identification; clinical investigation; clinical predictive model; cohort; cytokine; data integration; dysbiosis; extracellular; high risk population; imaging approach; improved; longitudinal design; member; metabolomics; microbial; microbiome; microbiota; mitochondrial metabolism; monocyte; mortality; multiple omics; novel therapeutics; pre-clinical; predictive modeling; prevent; programs; response; restraint; sample collection; systemic autoimmune disease; transcriptome sequencing; virome; young woman

Project Summary Systemic lupus erythematosus (SLE) is a heterogeneous, systemic autoimmune disease that causes significant morbidity and early mortality, especially in minority populations and in women of child-bearing age. By the time patients reach SLE classification, the majority exhibit organ/tissue damage and ongoing, aggressive inflammatory processes. Preventing SLE would reduce the risk of irreversible organ damage and treatment-related toxicities, but requires identification and validation of drivers and restraints of disease progression during this pre-/early-clinical time period. Our research groups have made important progress toward deciphering aspects of preclinical autoimmunity. A few findings include showing: autoantibodies occur in linked-subsets years before clinical disease, demonstrating humoral epitope spreading and peripheral immune dysregulation in preclinical autoimmune transition, defining immune endotypes of autoantibody positive healthy individuals, identifying activated B cell and select myeloid cell subsets preceding SLE disease flare, and establishing viral reactivation preceding SLE disease onset. Through our newly formed ADAPTS consortium, we will address these gaps with twelve available, complementary pre-disease unique collections that span this continuum from benign autoimmunity to active SLE, which includes clinical data, questionnaire information, biospecimens, autoantibody and other experimental data from nearly 11,000 participants. A subset of the highest-risk individuals earlier in this continuum will be followed for autoimmune and clinical progression. These cross-sectional collections are augmented with longitudinal transitional cohorts which include over 400 individuals who transition to SLE with pre-disease samples and clinical data. Our investigative team members bring strengths in clinical investigation, innate immunology, cell-free nucleic acid sensing, soluble mediator characterization, multi-omic analyses, cellular immunology, immune metabolism, systems immunology, bioinformatics and strong, productive collaborations. Building on our published and new preliminary data, our ADAPTS consortium of clinical and basic scientists will assess potentially independent or complementary mechanisms of disease progression and immune restraint by testing the roles of RNA-sensing pathways, cell-free nucleic acids, age-associated B cells and autoantibody characteristics, myeloid cell subsets, T cell lymphopenia and lymphopenia-induced proliferation, T cell immunometabolism, as well as select environmental (microbiome, virome), genomic and innate and adaptive immune responses as drivers of SLE disease. We will also validate and refine predictive models of clinical SLE disease development to inform future prevention trials and assist the field through molecular and clinical endotype identification of the preclinical time periods. Data from this integrated research program will inform targeted immune-mediated prevention trial development, selection of cellular/molecular and pathway-directed therapies, and the design of longitudinal SLE natural history or prevention studies.

项目概要 系统性红斑狼疮 (SLE) 是一种异质性、系统性自身免疫性疾病，可导致 发病率和早期死亡率很高，特别是在少数民族人口和育龄妇女中。 当患者达到 SLE 分类时，大多数患者表现出器官/组织损伤，并且持续存在， 侵袭性炎症过程。预防 SLE 将降低不可逆器官损伤的风险 与治疗相关的毒性，但需要识别和验证疾病的驱动因素和限制因素 在此临床前/早期阶段的进展。我们的研究小组取得了重要进展 破译临床前自身免疫的各个方面。一些发现包括显示： 出现自身抗体 在临床疾病发生前数年的连锁子集中，表现出体液表位扩散和外周 临床前自身免疫转变中的免疫失调，定义自身抗体的免疫内型 阳性健康个体，识别激活的 B 细胞并选择 SLE 疾病之前的骨髓细胞亚群 耀斑，并在系统性红斑狼疮疾病发作前确定病毒再激活。 通过我们新成立的 ADAPTS 联盟，我们将通过 12 个可用的、 补充病前独特的集合，跨越从良性自身免疫到主动免疫的连续体 SLE，包括临床数据、问卷信息、生物样本、自身抗体等 来自近 11,000 名参与者的实验数据。在此之前风险最高的个人的子集 将跟踪自身免疫和临床进展的连续体。这些横截面集合是 增加了纵向过渡队列，其中包括超过 400 名患有 SLE 的患者 病前样本和临床数据。我们的研究团队成员在临床研究方面具有优势， 先天免疫学、无细胞核酸传感、可溶性介质表征、多组学分析、 细胞免疫学、免疫代谢、系统免疫学、生物信息学等 合作。基于我们已发布的新初步数据，我们的 ADAPTS 临床和 基础科学家将评估疾病进展的潜在独立或补充机制 通过测试 RNA 传感途径、无细胞核酸、年龄相关 B 细胞的作用来抑制免疫 和自身抗体特征、骨髓细胞亚群、T 细胞淋巴细胞减少症和淋巴细胞减少症诱导的 增殖、T 细胞免疫代谢，以及选择环境（微生物组、病毒组）、基因组和 先天性和适应性免疫反应是 SLE 疾病的驱动因素。我们还将验证和完善预测 临床 SLE 疾病发展模型为未来的预防试验提供信息并通过以下方式协助该领域 临床前时间段的分子和临床内型鉴定。这项综合研究的数据 计划将告知有针对性的免疫介导的预防试验的开发、细胞/分子的选择 和路径导向治疗，以及纵向 SLE 自然史或预防研究的设计。