Contributions of autophagy-related genes in lupus

自噬相关基因在狼疮中的贡献

基本信息

批准号：
10682136
负责人：
Swapan K. Nath
金额：
$ 75.26万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682136
关键词：
3-Dimensional Acceleration Address Affect African American African American population Age Algorithms Alleles Animal Model Antigen-Antibody Complex Asian Asian Americans Asian population Autoantibodies Autoimmune Diseases Autoimmunity Autophagocytosis B-Lymphocytes Biochemical Biological Biological Assay Biology CDKN1B gene Catabolic Process Cell Line Cell physiology Cells Cellular biology Chromatin Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Crohn&apos s disease Cytoplasm DNA Resequencing Data Deposition Diagnosis Disease Drug Targeting Ethnic Origin Ethnic Population Etiology European European ancestry Follow-Up Studies Gender Genes Genetic Genetic Heterogeneity Genetic Transcription Genetic study Genotype Gifts Heritability High Prevalence Hispanic Americans Hispanic Populations Homeostasis Human IGA Glomerulonephritis Immune Immune System Diseases Individual Inflammation Inflammatory Intervention Kidney Knowledge Lead Life Link Linkage Disequilibrium Lupus Lupus Nephritis Lymphocyte Lysosomes Maps Mediating Metabolic stress Minority Groups Molecular Molecular Mechanisms of Action Morbidity - disease rate Multiple Sclerosis Nephritis Nucleic Acid Regulatory Sequences Organ Organelles Pathogenesis Pathogenicity Pathway interactions Patients Play Population Heterogeneity Predisposition Process Production Regulation Regulatory Element Reporting Research Resources Risk Role Sampling Signal Transduction Single Nucleotide Polymorphism Skin Structure Susceptibility Gene System Systemic Lupus Erythematosus T-Lymphocyte Targeted Resequencing Tissues Translating Variant Woman autoreactivity base editing causal variant chronic autoimmune disease clinical heterogeneity curative treatments disease phenotype effective therapy ethnic diversity ethnic minority follow-up genome wide association study kidney cell knockout gene misfolded protein mortality multi-ethnic multiorgan damage novel pathogenic autoantibodies podocyte protein degradation rare variant response risk variant sex synergism

项目摘要

ABSTRACT Lupus or systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease with a substantial genetic basis. SLE is characterized by abnormal T- and B-cell responses, production of numerous pathogenic autoantibodies, and immune complex deposition, leading to various clinical manifestations including multi-organ damage (e.g., kidneys, skin). SLE has disproportionate impacts based on gender and ethnicity. Approximately 90% of those affected are women. In addition, SLE has a 3-5-fold higher prevalence in Asian, African-American, and Hispanic individuals compared to those with European ancestry, as well as more severe clinical manifesta- tions, including organ damage (e.g., nephritis). Evidence from genetics, cell biology, and animal models suggests that autophagy, a major pathway for organelle and protein turnover, plays a pivotal role in SLE pathogenesis. Autophagy is a highly conserved lysosome-mediated catabolic process that removes unwanted cytoplasmic components (e.g., long-lived and/or misfolded proteins) and damaged organelles. This process maintains cellular homeostasis and survival under metabolic stress. Recent genome-wide association studies (GWAS) have linked autoimmune diseases, including SLE, to autophagy-related genes. However, there is currently a huge gap in defining causal relationships between associated variants and molecular mechanisms underlying SLE. This lack of knowledge about pathogenic effects underlying GWAS signals hinders translating GWAS discoveries into diagnosis and treatment. To address this issue, we selected six highly ranked, well-replicated loci; four of them were initially discovered in Asian populations, two we previously reported as novel loci for SLE susceptibility. We have assembled a research team with the expertise and resources to discover and mechanistically characterize functional variants linked to SLE. We hypothesize that at each GWAS locus, both common and rare variants contribute to SLE risk by affecting expression of autophagy genes through tissue-specific regulatory elements. Aim 1 will identify SLE-predisposing variants using a comprehensive imputation-based analysis of combined novel resequencing data from SLE patients and controls in addition to our previous fine-mapping of four ethnically diverse populations. Functional variants will be prioritized by allele-specific expression, open chromatin, and 3D interaction data from immune cells. We will elucidate genetic and clinical heterogeneity of SLE by assessing association of identified variants with SLE and its clinical manifestations and autoantibody profiles. Associated variants, especially imputed and rare variants, will be validated through follow-up genotyping. Aim 2 will define the mechanistic and functional consequences of SLE-predisposing variants using appropriate functional assays, including CRISPR-based gene knock-out and base-editing in cell lines (Jurkat, Toledo, podocyte, HEK293) and primary immune cells (T- and B-cells) relevant to SLE. Thus, we will uncover functional variants underlying SLE association signals, and illuminate mechanisms by which these variants contribute to lupus and its clinical manifestations. Through this approach, our analysis should yield novel targets for potential clinical interventions.

抽象的狼疮或全身性红斑狼疮（SLE）是一种潜在的致命自身免疫性疾病，很大遗传基础。 SLE的特征是异常T和B细胞反应，产生众多致病性自身抗体和免疫复合物沉积，导致各种临床表现，包括多器官损坏（例如，肾脏，皮肤）。 SLE基于性别和种族具有不成比例的影响。大约受影响的人中有90％是女性。此外，SLE在亚裔，非裔美国人的患病率高3-5倍与欧洲血统的人相比，西班牙裔人以及更严重的临床表现包括器官损伤（例如肾炎）。遗传学，细胞生物学和动物模型的证据表明这种自噬是细胞器和蛋白质更新的主要途径，在SLE发病机理中起关键作用。自噬是一种高度保守的溶酶体介导的分解代谢过程，可去除不良的细胞质成分（例如，长寿命和/或错误折叠的蛋白质）和细胞器受损。这个过程保持细胞在代谢压力下的稳态和生存。最近全基因组关联研究（GWAS）已连接包括SLE在内的自身免疫性疾病与自噬相关基因。但是，目前存在很大的差距定义SLE上的相关变体与分子机制之间的因果关系。这个缺乏关于GWAS基础致病作用的知识，将GWAS发现转化为诊断和治疗。为了解决这个问题，我们选择了六个高度排名，重复良好的基因座。他们四个最初是在亚洲人群中发现的，我们以前曾报道过两个用于SLE敏感性的新基因座。我们已经组建了一个研究团队，具有专业知识和资源，以发现和机械的特征链接到SLE的功能变体。我们假设在每个GWAS基因座，无论是常见和稀有变体通过组织特异性调节元件影响自噬基因的表达来促进SLE风险。 AIM 1将使用全面的基于基于的合并的分析来识别SLE-prodisposing变体除了我们先前的四个种族绘图外，还可以从SLE患者和对照组中重新陈述数据多样化的人群。功能变体将通过等位基因特异性表达，开放染色质和3D优先考虑来自免疫细胞的相互作用数据。我们将通过评估SLE的遗传和临床异质性鉴定出的变体与SLE及其临床表现和自身抗体谱的关联。联系变体，尤其是估算和稀有变体，将通过后续基因分型来验证。 AIM 2将定义使用适当的功能测定法的SLE-PREDISPODISS变体的机械和功能后果，包括基于CRISPR的基因敲除和细胞系中的基础编辑（Jurkat，Toledo，Podocyte，HEK293）和与SLE相关的原代免疫细胞（T和B细胞）。因此，我们将发现SLE上的功能变体关联信号和照明这些变体有助于狼疮及其临床的机制表现。通过这种方法，我们的分析应产生潜在临床干预措施的新目标。