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.

项目摘要 全身性红斑狼疮（SLE）是一种异质的全身自身免疫性疾病，引起 显着的发病率和早期死亡率，尤其是在少数族裔和育儿妇女中。 到患者达到SLE分类时，大多数表现出器官/组织损伤和持续 积极的炎症过程。防止SLE会降低不可逆器官损坏的风险，并 与治疗相关的毒性，但需要鉴定和验证驱动因素和疾病的限制 在此前/早期临床期间的进展。我们的研究小组取得了重要的进步 致力于解密临床前自身免疫的方面。一些发现包括显示：自动抗体发生 在临床疾病前几年的链接吸收器中，表现出体外表位扩散和周围 临床前自身免疫过渡中的免疫失调，定义自身抗体的免疫内型 阳性健康个体，鉴定活化的B细胞并选择SLE病之前的髓样细胞子集 耀斑，并在SLE病发作之前建立病毒重新激活。 通过我们新成立的Adapts联盟，我们将使用十二个可用的差距来解决这些差距， 从良性自身免疫到活动的互补前疾病的独特收藏 SLE，其中包括临床数据，问卷信息，生物测量，自身抗体和其他 来自近11,000名参与者的实验数据。在此之前的最高风险个人的子集 将遵循自身免疫性和临床进展的连续体。这些横截面收集是 加强纵向过渡队列，其中包括400多名过渡到SLE的个人 疾病前样品和临床数据。我们的调查团队成员为临床调查带来了优势， 先天免疫学，无细胞核酸感应，可溶性介体表征，多摩尼克分析， 细胞免疫学，免疫代谢，系统免疫学，生物信息学和强大的生产力 协作。在我们已发表的新初步数据的基础上，我们的临床财团和 基础科学家将评估疾病进展的潜在独立或互补机制， 通过测试RNA传感途径，无细胞核酸，与年龄相关的B细胞的作用，免疫约束 和自身抗体特征，髓样细胞亚群，T细胞淋巴细胞减少症和淋巴细胞减少症诱导的 增殖，T细胞免疫代谢以及精选的环境（微生物组，病毒群），基因组和 先天和适应性免疫反应是SLE病的驱动因素。我们还将验证和完善预测 临床SLE疾病开发模型，以告知未来的预防试验并通过 临床前时间的分子和临床内型鉴定。这项综合研究的数据 程序将为靶向免疫介导的预防试验开发，细胞/分子的选择提供信息 和途径定向疗法，以及纵向SLE自然史或预防研究的设计。