Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core Admin Supplement: Preclinical Studies in Sjogren's

加速药物合作 - 自身免疫和免疫疾病组织研究核心管理补充：干燥病的临床前研究

• 批准号: 10834635
• 负责人: Joel Marvin Guthridge
• 金额: $ 146.04万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-23 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10834635
• 关键词: Acceleration; Address; Affect; Algorithms; Antibodies; Antigens; Arthritis; Autoantibodies; Autoimmune Diseases; Automobile Driving; Autophagocytosis; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Biological Markers; Biological Response Modifier Therapy; Biopsy; Blood; CCR6 gene; CD4 Positive T Lymphocytes; CRISPR interference; CRISPR-mediated transcriptional activation; CXCR3 gene; Cell Death; Cell Separation; Cells; Chromium; Chronic; Classification; Clinic; Clinical; Clinical Trials; Cluster Analysis; Conduct Clinical Trials; Cytometry; Data; Data Set; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dryness; Economic Burden; Enhancers; Ensure; Epithelial Cells; Epithelium; Exclusion; Fatigue; Fibroblasts; Fibrosis; Flow Cytometry; Functional disorder; Genetic; Genomics; Gland; Goals; HLA-DR Antigens; Haplotypes; Heterogeneity; Human; Image; Immune; Immune System Diseases; Immunology; In Vitro; Individual; Interview; Investigation; Labial Salivary Gland; Lip structure; Lung; Lymphocyte; Lymphoma; Machine Learning; Maps; Medicine; Methods; Molecular; Monitor; Multiomic Data; Nature; Neuropathy; Pain; Pathogenicity; Pathology; Patient Recruitments; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Population; Positioning Attribute; Probability; Process; Proteins; Proteome; Proteomics; Research; Research Personnel; Rheumatism; Rheumatology; Risk; Role; SS-A antibodies; Saliva; Salivary Glands; Serum; Sialadenitis; Sjogren' s Syndrome; Sorting; Source; Surrogate Markers; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Telephone; Testing; Tissues; Transcriptional Regulation; Untranslated RNA; Vasculitis; Xerostomia; antibody diagnostic; autoimmune exocrinopathy; cell type; clinical development; clinical heterogeneity; cohort; data reduction; deep learning; diagnostic accuracy; diagnostic assay; diagnostic biomarker; disorder control; eye dryness; feature selection; genetic association; gradient boosting; health care settings; improved; insight; machine learning method; meetings; multidisciplinary; multiple omics; multiplex diagnostics; nano-string; neural network; new therapeutic target; noninvasive diagnosis; novel; patient subsets; preclinical study; programmed cell death protein 1; random forest; rheumatologist; risk variant; screening; single-cell RNA sequencing; support vector machine; tool; transcriptome; transcriptomics

PROJECT ABSTRACT Sjögren’s syndrome (SS) is an incapacitating rheumatic disease typified by severe dry eyes and mouth, often including arthritis, debilitating fatigue, pulmonary involvement, neuropathy, vasculitis and malignant lymphoma. The personal and economic burdens ($35 billion/year in the US) are high, and there is no effective biologic therapy. Lack of understanding of basic disease processes, molecular underpinnings of patient heterogeneity, and effective diagnostic biomarkers have hindered the development of effective biologic therapies and conduct of successful clinical trials. This is especially true for patients lacking anti-Ro antibodies (Ro– SS) who require a salivary gland biopsy for classification. We are in a unique position to study the differences between Ro+ and Ro– SS. In our carefully phenotyped cohort, nearly 40% of SS patients meeting current classification criteria lack diagnostic anti-Ro autoantibodies. Our Ro– SS cases have more glandular, articular, and pulmonary involvement than Ro+ SS cases, yet these patients are often not diagnosed by rheumatologists or included in clinical trials. Herein, we leverage our multidisciplinary team of investigators with expertise in rheumatology, immunology, genomics/genetics, as well as our carefully phenotyped cohort of 668 SS cases and 925 non-SS sicca patients to address these deficiencies. The project is based on compelling preliminary data identifying common and unique features in both Ro+ and Ro– SS groups and will study a common set of 60 Ro+ SS cases, 60 Ro– SS cases, and 24 healthy controls. Aim 1 will develop and apply an autoantibody-based diagnostic test for Ro– and Ro+ SS and leverage salivary gland proteomics, spectral flow cytometry, imaging mass cytometry, and functional studies to clarify the role of T and B cell subsets in disease. Aim 2 will employ single cell RNA-seq of PBMC and sorted cells studied in Projects 1 and 2, identify chromosomal interactions in primary salivary gland epithelial cells, study functional effects of Ro+ and Ro– SS risk alleles and long non-coding RNAs using CRISPR interference or activation for enhancers, and use feature selection and machine learning to identify sources of heterogeneity between Ro+ and Ro– SS.

项目摘要 干燥综合征（SS）是一种失能性风湿性疾病，其典型特征是严重的眼干燥和口干燥， 包括关节炎、使人衰弱的疲劳、肺部受累、神经病、血管炎和恶性淋巴瘤。 个人和经济负担（美国每年350亿美元）很高，而且没有有效的生物制剂。 疗法缺乏对基本疾病过程的理解，患者异质性的分子基础， 有效的诊断生物标志物阻碍了有效的生物疗法和行为的发展， 成功的临床试验。这对于缺乏抗Ro抗体（Ro-SS）的患者尤其如此， 唾液腺活检进行分类。我们处于一个独特的位置，可以研究Ro+和 反间谍组织。在我们仔细分型的队列中，近40%符合当前分类标准的SS患者缺乏 诊断性抗Ro自身抗体。我们的Ro-SS病例有更多的腺体、关节和肺部受累 然而，这些患者往往没有被风湿病学家诊断或纳入临床试验。 在这里，我们利用我们的多学科团队的研究人员与专业知识，在风湿病学，免疫学， 基因组学/遗传学，以及我们仔细分型的668例SS病例和925例非SS干燥症患者队列 来弥补这些缺陷。该项目基于令人信服的初步数据， Ro+和Ro- SS组的独特特征，并将研究一组常见的60例Ro+ SS病例，60例Ro- SS病例， 24例健康对照。目标1将开发和应用一种基于自身抗体的Ro和 Ro+ SS并利用唾液腺蛋白质组学、光谱流式细胞术、成像质谱细胞术和功能性 研究阐明T和B细胞亚群在疾病中的作用。目的2将采用PBMC的单细胞RNA-seq， 在项目1和2中研究的分选细胞，鉴定初级唾液腺上皮细胞中的染色体相互作用， 细胞，使用CRISPR研究Ro+和Ro-SS风险等位基因和长非编码RNA的功能效应 干扰或激活增强子，并使用特征选择和机器学习来识别 Ro+和Ro- SS之间的异质性。