Sjögren's International Collaborative Clinical Alliance Next Generation Studies (SICCA-NextGen)

干燥国际合作临床联盟下一代研究 (SICCA-NextGen)

• 批准号: 10630362
• 负责人: CAROLINE Helene SHIBOSKI
• 金额: $ 80.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630362
• 关键词: Advisory Committees; American; Autoimmune Diseases; Biological; Biological Markers; Biological Process; Biological Specimen Banks; Biopsy; Cells; Classification; Clinical; Clinical Data; Clinical Trials; Collaborations; Communities; DNA Methylation; Data; Data Set; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Epidemiology; Epigenetic Process; Etiology; European; Funding; Future; Gene Expression; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic study; Genomics; Genotype; Geography; Growth; Hereditary Disease; Hypergammaglobulinemia; Immune response; Immunology; Infrastructure; International; Labial Salivary Gland; Laboratories; Lymphocyte; Messenger RNA; Methods; Methylation; MicroRNAs; Modification; Molecular; National Institute of Dental and Craniofacial Research; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phenotype; Population Heterogeneity; Positioning Attribute; Process; Protocols documentation; Registries; Research; Research Design; Research Personnel; Resources; Rheumatism; Rheumatology; Salivary Gland Tissue; Sialadenitis; Signs and Symptoms; Sjogren' s Syndrome; Specimen; Standardization; Structure of germinal center of lymph node; Therapeutic; Time; Tissues; United States National Institutes of Health; Validation; Work; biobank; cohort; college; data repository; data standards; database of Genotypes and Phenotypes; epigenome; follow-up; genetic epidemiology; genome wide association study; genome-wide; improved; insight; next generation; novel marker; participant enrollment; phenotypic data; promoter; repository; response; sample collection; single cell mRNA sequencing; success; transcriptome; transcriptomics; treatment research; whole genome

ABSTRACT The Sjögren’s International Collaborative Clinical Alliance (SICCA) was established in 2003 to improve the understanding, diagnosis and treatment of patients with Sjögren’s syndrome (SS) by 1) developing/validating standardized classification criteria for SS; and 2) developing a longitudinal data and biospecimen repository that could be used by the research community for future epidemiologic, pathogenesis, and genetic studies of SS. Using rigorous study design and, standardized data/specimen collection protocols, SICCA investigators from nine leading academic research groups across the globe assembled a unique biorepository from a cohort of 3,514 participants with extremely well characterized phenotypic data (with follow-up data/specimens on 771). Multiple deliverables were achieved including 1) development and validation of classification criteria for SS provisionally approved by the American College of Rheumatology (ACR) in 2011 (followed by the development/validation of a set of classification criteria approved by ACR and EULAR in 2016); 2) a Genome-Wide Association Study that highlighted the genetic heterogeneity of SS according to ancestry, and established a unique genetic repository for SS available for public use through dbGAP; and 3) a dissemination plan, which has yielded important new findings regarding the SS phenotype. In response to FOA PAR-17-154, our proposal leverages unique NIDCR-funded resources by utilizing existing infrastructure and an expanded team, and positions us to exploit recent explosive growth in the fields of immunology, genomics and epigenetics to better understand the pathogenesis of SS and identify therapeutic pathways, and new biomarkers. Using previously collected clinical data/biospecimens, and genome-wide genotyping performed on all participants, we propose to define the transcriptomics and epigenetics of SS at the cell and tissue levels. This will enhance the SICCA registry by generating genome-wide DNA methylation and whole-genome sequencing of single-cell mRNA, bulk mRNA, and miRNA and enable high impact studies of underlying biologic pathways of SS. Given the relationship between the epigenome and gene expression, specific epigenetic modifications and transcriptomic profiles may represent novel biomarkers in autoimmune diseases. We also propose an expanded dissemination plan that can leverage these omics data sets thereby engaging SS investigators worldwide in discovery. We aim to 1) Generate transcriptome and methylation profiles in order to explore transcriptomic diversity across subsets of SICCA participants with well characterized epigenetic and genetic profiles, across cell and tissue types; 2) Explore correlations between omics profiles and signs of severe disease manifestations, including presence of germinal-center-formation (GCF) and focal lymphocytic sialadenitis with a high focus score in LSG biopsies, hypergammaglobulinemia, and hypocomplementemia; and 3) Characterize longitudinal changes in omics profiles of subsets of SICCA patients. While traditional phenotypic features of SS are stable, we hypothesize that omics profiles may be more dynamic across time, providing insight into biologic processes associated with disease progression and outcome.

抽象的 Sjögren 国际合作临床联盟 (SICCA) 成立于 2003 年，旨在改善 通过 1) 开发/验证来了解、诊断和治疗干燥综合征 (SS) 患者 SS 标准化分类标准； 2) 开发纵向数据和生物样本存储库 研究界可以将其用于未来 SS 的流行病学、发病机制和遗传学研究。使用 严格的研究设计和标准化的数据/样本收集协议，来自九个国家的 SICCA 研究人员 全球领先的学术研究小组从 3,514 人的队列中组建了一个独特的生物样本库 具有极其明确的表型数据特征的参与者（771 的后续数据/样本）。多种的 已实现的可交付成果包括 1) 制定和验证 SS 临时分类标准 2011 年获得美国风湿病学会 (ACR) 批准（随后开发/验证了 2016 年 ACR 和 EULAR 批准的一套分类标准）； 2）全基因组关联研究 强调了 SS 根据祖先的遗传异质性，并建立了一个独特的遗传库 SS 可通过 dbGAP 供公众使用； 3）一项传播计划，该计划产生了重要的新发现 关于SS表型。为了响应 FOA PAR-17-154，我们的提案利用了由 NIDCR 资助的独特项目 通过利用现有基础设施和扩大的团队来资源，并使我们能够利用最近的爆炸性 免疫学、基因组学和表观遗传学领域的发展，以更好地了解 SS 和 确定治疗途径和新的生物标志物。使用之前收集的临床数据/生物样本，以及 对所有参与者进行全基因组基因分型，我们建议定义转录组学和表观遗传学 细胞和组织水平上的SS。这将通过生成全基因组 DNA 来增强 SICCA 注册表 单细胞 mRNA、bulk mRNA 和 miRNA 的甲基化和全基因组测序，实现高影响 SS 潜在生物学途径的研究。鉴于表观基因组和基因之间的关系 表达、特定的表观遗传修饰和转录组谱可能代表新的生物标志物 自身免疫性疾病。我们还提出了一个可以利用这些组学数据集的扩展传播计划 从而让世界各地的党卫军调查员参与发现。我们的目标是 1) 生成转录组和甲基化 概况，以探索具有良好特征的 SICCA 参与者子集的转录组多样性 跨细胞和组织类型的表观遗传和遗传特征； 2) 探索组学概况与 严重疾病表现的体征，包括生发中心形成（GCF）和局灶性的存在 LSG 活检中焦点评分高的淋巴细胞性唾液腺炎、高丙种球蛋白血症和 低补体血症； 3) 表征 SICCA 患者亚组组学特征的纵向变化。 虽然 SS 的传统表型特征是稳定的，但我们假设组学特征可能更加动态 跨越时间，提供与疾病进展和结果相关的生物过程的见解。

项目成果

Identification of Sjögren's syndrome patient subgroups by clustering of labial salivary gland DNA methylation profiles.

• DOI: 10.1371/journal.pone.0281891
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7

Associations Between Smoking and Primary Sjögren Syndrome Classification Using the Sjögren's International Collaborative Clinical Alliance Cohort.

• DOI: 10.1002/acr2.11362
• 发表时间: 2022-03
• 期刊: ACR open rheumatology
• 影响因子: 3.4
• 作者: Gebreegziabher EA;Oldenburg CE;Shiboski SC;Baer AN;Jordan RC;Rose-Nussbaumer JR;Bunya VY;Akpek EK;Criswell LA;Shiboski CH;Lietman TM;Gonzales JA
• 通讯作者: Gonzales JA

Sjögren's Versus Non-Sjögren's Ocular Features: Similar Symptoms, But Significantly Worse Signs.

• DOI: 10.1167/iovs.65.1.23
• 发表时间: 2024-01-02
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4

Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren's syndrome.

• DOI: 10.1371/journal.pone.0248429
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chi C;Taylor KE;Quach H;Quach D;Criswell LA;Barcellos LF
• 通讯作者: Barcellos LF