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

基本信息

批准号：
10470853
负责人：
Christopher J Lessard
金额：
$ 74.83万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
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/10470853
关键词：
Acinar Cell Affect American Antigen Presentation Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes Bioinformatics Biological Markers Biological Products 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 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 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 Rheumatism Ribonucleoproteins Risk Risk Factors Role STAT4 gene Salivary Gland Tissue Salivary Glands Sample Size Sampling Signal Transduction Sjogren&apos s Syndrome Specificity Stratification Study Subject Suggestion Surrogate Markers T-Lymphocyte TYK2 Technology Testing Time Tissue Banks Tissues Variant Work accurate diagnostics base causal variant cell type clinical translation cohort cytokine diagnostic tool disease heterogeneity falls gene discovery genetic architecture genetic association genetic risk factor genome wide association study high risk innovation insight lymphocyte trafficking molecular marker monocyte new therapeutic target novel overexpression pathogenic autoantibodies patient biomarkers patient stratification patient subsets peripheral blood phenotypic data response risk variant targeted treatment therapeutic target tool transcriptomics

项目摘要

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. !

抽象的干燥综合征 (SS) 是一种复杂的风湿性疾病，其特征是外分泌的自身免疫性靶向严重的临床表现可能包括使人衰弱的干燥、肺功能障碍、神经病、广泛的疲劳和淋巴瘤涉及激活导管和腺泡上皮细胞的病变。 SS 的诊断和治疗非常困难。我们的团队领导着由 26 个 SS 研究小组组成的国际干燥遗传学网络 (SGENE) SGENE 研究致力于了解 SS 的遗传结构，已确定 16 种 SS 风险中的 15 种。迄今为止在欧洲人群中建立的 SS 风险位点在 I 型和 II 型干扰素中合并。 (IFN)、NFkB 信号传导、抗原呈递、自身抗体产生和淋巴细胞运输途径。遗传学研究提供了强有力的证据支持各种先天和然而，适应性免疫细胞亚群，这些细胞类型如何在功能上受到 SS 风险等位基因的影响仍然存在重要的是，这些研究还提出了新的治疗靶点，例如 IL12 信号传导。哪些生物疗法已被开发用于相关自身免疫性疾病，但以前没有被考虑过 SS 中 2,809 个 SS 病例的初步数据表明，还有超过 40 个候选位点值得进一步研究。根据我们的遗传学研究的见解，我们开发了一种新的疾病发病机制模型，可以区分基于不同分子机制的 3 个主要患者亚型我们的总体目标是开发更多的患者亚型。 SS 遗传决定因素的完整模型，并识别反映不同分子的生物标志物我们的疾病模型中所代表的机制可以开发成对患者进行分层的临床工具。在目标 1 中，我们将利用我们独特的途径极大地扩展我们当前的全基因组关联研究来自特征明确的 SGENE 队列（> 10,000 例 SS 病例）的样本、实验室和临床数据。我们将测试已知的 SS 风险变异体对唾液腺组织转录的细胞特异性顺式调节作用。从分类为 3 个主要患者的受试者 (n = 200) 的小唇腺活检中获取的组织库我们提出的疾病模型中定义的子集，加上淋巴瘤患者和对照的子集将是将利用空间转录组技术来生成基因表达数据，其中在目标 3 中，我们将整合遗传、转录组学，以接近单细胞的分辨率保留形态学背景。和蛋白质组数据来开发可溶性免疫介质的多维面板，这些介质可用作外周血这些患者亚组的生物标志物有助于患者分层，这些研究将扩大我们的范围。了解 SS 的遗传因素，识别细胞特异性功能对转录的影响，促进开发新的临床工具以实现更准确的诊断，并建立快速临床的可行性使用新型和现有的生物制剂定向转化为明确定义的治疗患者亚群的靶向针对驱动这种复杂自身免疫性疾病的途径和细胞类型。！