Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

干燥综合征遗传风险位点的发现和表征

• 批准号: 10052910
• 负责人: Christopher J Lessard
• 金额: $ 74.9万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10052910
• 关键词: Acinar Cell; Affect; American; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Bioinformatics; Biological; Biological Markers; Biological Response Modifier Therapy; Biological Response Modifiers; Biopsy; Blood Banks; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Complex; Coupled; Data; Dendritic Cells; Development; Diagnosis; Diagnostic; Disease; Disease model; Dryness; Duct (organ) structure; Ductal Epithelial Cell; Epithelial Cells; European; Exhibits; Exocrine Glands; Fatigue; Feedback; Fostering; Functional disorder; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Genomic Segment; Gland; Goals; Hematologic Neoplasms; Histologic; IL12A gene; Immune; Immune response; Immune system; Interferon Type II; Interferons; Interleukin-12; International; Knowledge; Laboratories; Lacrimal gland structure; Lead; Lesion; Life; Light; Link; Lung; Lung diseases; Lymphocyte; Lymphoma; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Methodology; Minor; Modeling; Molecular; Morphology; Natural Killer Cells; Neurologic; Neuropathy; Organ; Outcome; PRDM1 gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Care; Patient Rights; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Plant Roots; Population; Production; Proteomics; Publishing; Quantitative Trait Loci; Research; Resolution; Ribonucleoproteins; Risk; Risk Factors; Role; STAT4 gene; Salivary Gland Tissue; Salivary Glands; Sample Size; Sampling; Signal Transduction; Sjogren' s Syndrome; Specificity; Stratification; Study Subject; Suggestion; Surrogate Markers; T-Lymphocyte; TYK2; Technology; Testing; Time; Tissue Banks; Tissues; Variant; Work; base; causal variant; cell type; clinical translation; cohort; cytokine; disease heterogeneity; falls; gene discovery; genetic architecture; genetic association; genetic risk factor; genome wide association study; high risk; innovation; insight; molecular marker; monocyte; new therapeutic target; novel; overexpression; patient biomarkers; patient stratification; patient subsets; peripheral blood; phenotypic data; response; risk variant; targeted treatment; therapeutic target; tool; trafficking; transcriptomics

ABSTRACT Sjögren’s syndrome (SS) is a complex rheumatic disorder distinguished by autoimmune targeting of exocrine glands. Severe clinical manifestations may include debilitating dryness, pulmonary dysfunction, neuropathies, profound fatigue, and lymphoma. Salivary gland lesions involve activated ductal and acinar epithelial cells as well as irreversible immune-mediated tissue damage. Diagnosis and treatment of SS are notoriously difficult. Our group leads the international Sjögren’s Genetics Network (SGENE) comprised of 26 SS research groups dedicated to understanding the genetic architecture of SS. SGENE studies have identified 15 of the 16 SS risk loci thus far established in European-derived populations. SS risk loci coalesce in Type I and Type II interferon (IFN), NFkB signaling, antigen presentation, autoantibody production and lymphocyte trafficking pathways. Our genetic studies have provided strong evidence supporting a pathogenic role in SS from various innate and adaptive immune cell subsets, however, how these cell types are functionally affected by SS risk alleles remain poorly understood. Importantly, these studies also suggest new therapeutic targets, such as IL12 signaling, for which biologic therapies have been developed for related autoimmune diseases, but not previously considered in SS. Preliminary data in 2,809 SS cases suggest >40 additional candidate loci that warrant further study. Using insights from our genetic studies, we have developed a novel model of disease pathogenesis that differentiates 3 major patient subsets based on distinct molecular mechanisms. Our overall goals are to develop a more complete model of SS genetic determinants and to identify biomarkers that reflect the distinct molecular mechanisms represented in our disease model that could be developed into clinical tools for stratifying patients. In Aim 1, we will greatly expand our current genome-wide association studies by leveraging our unique access to samples, laboratory and clinical data from well-characterized SGENE cohorts (>10,000 SS cases). In Aim 2, we will test known SS risk variants for cell specific cis-regulatory effects on transcription in salivary gland tissues. Banked tissues obtained from minor labial gland biopsies from subjects (n=200) classified into the 3 major patient subsets defined in our proposed disease model, plus a subset of patients with lymphoma and controls will be evaluated. Spatial transcriptomic technologies will be utilized to generate gene expression data in which morphological context is retained at nearly single cell resolution. In Aim 3, we will integrate genetic, transcriptomic and proteomic data to develop multidimensional panels of soluble immune mediators that can serve as peripheral biomarkers for these patient subgroups to facilitate patient stratification. These studies will expand our understanding of genetic contributors to SS, identify cell-specific functional effects on transcription, foster development of new clinical tools for more accurate diagnostics, and establish the feasibility of rapid clinical translation for therapeutic targeting in well-defined patient subsets using novel and existing biologics directed against pathways and cell types that drive this complex autoimmune disorder. !

摘要 干燥综合征(SS)是一种复杂的风湿性疾病，以自身免疫靶向外分泌为特征 腺体。严重的临床表现可能包括虚弱干燥、肺功能障碍、神经病变、 极度疲劳和淋巴瘤。涎腺病变涉及激活的导管和腺泡上皮细胞 以及不可逆转的免疫介导的组织损伤。SS的诊断和治疗是出了名的困难。 我们小组领导着由26个党卫军研究小组组成的国际Sjögren‘s Genetics Network(SGENE 致力于了解SS的遗传结构。SGENE研究已经确定了16种SS风险中的15种 到目前为止，在欧洲派生的种群中已经建立了基因座。I型和II型干扰素合并SS风险基因座 干扰素、NFkB信号转导、抗原提呈、自身抗体产生和淋巴细胞转运途径。我们的 遗传学研究提供了强有力的证据支持SS的致病作用，这些作用来自于各种先天和 适应性免疫细胞亚群，然而，这些细胞类型如何受到SS风险等位基因的功能影响仍然存在 人们对此知之甚少。重要的是，这些研究还提出了新的治疗靶点，如IL12信号转导， 哪些生物疗法已被开发用于相关的自身免疫性疾病，但以前没有考虑过 在党卫军。2,809个SS病例的初步数据建议&gt；40个值得进一步研究的候选基因座。vbl.使用 从我们的基因研究中得到的启示，我们已经开发出一种新的疾病发病机制模型，它区分了 基于不同分子机制的3个主要患者亚群。我们的总体目标是开发出更多 SS遗传决定因素的完整模型和识别反映不同分子的生物标志物 在我们的疾病模型中所代表的机制，可以发展成对患者进行分层的临床工具。 在目标1中，我们将通过利用我们独特的访问方式，极大地扩展我们目前的全基因组关联研究 样本、实验室和临床数据来自具有良好特征的SGENE队列(&gt；10,000例SS病例)。在目标2中， 我们将测试已知的SS风险变种对唾液腺组织转录的细胞特异性顺式调节效应。 从三个主要患者的受试者(n=200)的小唇腺活检中获得的银行组织 在我们建议的疾病模型中定义的子集，加上淋巴瘤患者和对照组的子集将是 已评估。空间转录技术将被用来产生基因表达数据，其中 形态背景保持在几乎单一的细胞分辨率。在目标3中，我们将整合基因、转录本 和蛋白质组数据来开发可用作外周细胞的可溶性免疫介质的多维面板 这些患者亚组的生物标记物有助于患者分层。这些研究将扩大我们的 了解SS的遗传贡献者，确定细胞对转录的特定功能影响，促进 开发新的临床工具，以获得更准确的诊断，并建立快速临床的可行性 使用新的和现有的生物制剂指导在明确定义的患者亚群中进行治疗靶向的翻译 对抗驱动这种复杂的自身免疫性疾病的途径和细胞类型。 好了！