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

项目摘要 干燥综合征(SS)是一种以严重的眼睛和口腔干燥为特征的风湿性疾病，通常 包括关节炎、衰弱乏力、肺部受累、神经病变、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 心理治疗。缺乏对基本疾病过程的了解，缺乏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治疗和传导的发展 成功的临床试验。对于缺乏抗Ro抗体(Ro-SS)的患者尤其如此，他们需要 唾液腺活检用于分类。我们处于一个独特的位置来研究Ro+和Ro+之间的差异 RO-SS。在我们仔细研究的表型队列中，符合当前分类标准的近40%的SS患者缺乏 诊断抗Ro自身抗体。我们的RO-SS病例有更多的腺体、关节和肺受累。 与Ro+SS病例相比，这些患者往往不被风湿科医生诊断或纳入临床试验。 在此，我们利用我们的多学科研究团队，拥有风湿学、免疫学、 基因组学/遗传学，以及我们对668例SS患者和925名非SS Sicca患者的仔细表型队列 解决这些不足之处。该项目基于令人信服的初步数据，确定了共同和 Ro+和Ro-SS组的独特特征，并将研究60例Ro+SS病例，60例Ro-SS病例 病例组和24例健康对照组。AIM 1将开发和应用一种基于自身抗体的Ro-和Ro-And诊断测试 RO+SS和杠杆唾液腺蛋白质组学、光谱流式细胞术、成像质量细胞术和功能 研究阐明T和B细胞亚群在疾病中的作用。AIM 2将采用PBMC的单细胞RNA-SEQ和 在项目1和2中研究的分类细胞，确定了原始唾液腺上皮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 干扰或激活增强剂，并使用特征选择和机器学习来识别 Ro+和Ro-SS的异质性。

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.