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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.

摘要