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：
10256035
负责人：
Christopher J Lessard
金额：
$ 73.52万
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/10256035
关键词：
Acinar Cell Affect American Antigen Presentation Autoantibodies Autoimmune Autoimmune Diseases 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 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 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 Sjögren综合征（SS）是一种复杂的风湿病，通过自身免疫性靶向外分泌腺体。严重的临床表现可能包括使干燥，肺部功能障碍，神经病，神经病，深刻的疲劳和淋巴瘤。唾液腺病变涉及活化的导管和腺泡上皮细胞作为以及不可逆的免疫介导的组织损伤。众所周知，SS的诊断和治疗是困难的。我们的小组领导国际Sjögren的遗传网络（SGENE）完成了26个SS研究小组致力于理解SS的遗传结构。 Sgene研究已经确定了16个SS风险中的15个迄今为止，基因座在欧洲衍生的人群中建立。 SS风险基因座结合I型和II型干扰素（IFN），NFKB信号传导，抗原表现，自身抗体产生和淋巴细胞运输途径。我们的遗传学研究提供了有力的证据，支持来自各种先天和的SS中的致病作用但是，自适应免疫细胞子集，但是，这些细胞类型在功能上如何受SS风险等位基因影响理解不佳。重要的是，这些研究还提出了新的治疗靶标，例如IL12信号传导针对相关自身免疫性疾病开发了哪种生物疗法，但以前尚未考虑在SS中。 2,809例SS病例中的初步数据表明> 40个其他候选基因座，需要进一步研究。使用从我们的遗传研究中的见解，我们开发了一种新型的疾病发病机理模型，以区分基于不同分子机制的3个主要患者子集。我们的总体目标是开发更多 SS遗传确定剂的完整模型，并确定反映不同分子的生物标志物我们疾病模型中代表的机制可以发展为用于分层患者的临床工具。在AIM 1中，我们将通过利用我们独特的访问来大大扩展我们当前的全基因组协会研究来自特征良好的Sgene同类群的样品，实验室和临床数据（> 10,000个SS病例）。在AIM 2中，我们将测试已知的SS风险变体，以针对细胞特异性顺式调节对唾液腺组织转录的影响。从分类为3个主要患者的受试者（n = 200）的次要唇腺活检获得的库存组织在我们提出的疾病模型中定义的子集，以及一部分淋巴瘤和对照组的子集将是评估。空间转录组技术将用于生成基因表达数据，其中形态学环境几乎保留在几乎单个细胞分辨率下。在AIM 3中，我们将整合遗传，转录组和蛋白质组学数据以开发可作为外围的固体免疫介质的多维面板这些患者亚组的生物标志物促进患者分层。这些研究将扩大我们的了解SS的遗传因素，鉴定细胞特异性功能对转录，促进开发新的临床工具以进行更准确的诊断，并确定快速临床的可行性使用新颖和现有的生物制剂指导的定义明确的患者子集的治疗靶向靶向的翻译针对驱动这种复杂自身免疫性疾病的途径和细胞类型。呢