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:
- 金额:$ 75.26万
- 依托单位:
- 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:
- 关键词:3-DimensionalAccelerationAddressAffectAfrican AmericanAfrican American populationAgeAlgorithmsAllelesAnimal ModelAntigen-Antibody ComplexAsianAsian AmericansAsian populationAutoantibodiesAutoimmune DiseasesAutoimmunityAutophagocytosisB-LymphocytesBiochemicalBiologicalBiological AssayBiologyCDKN1B geneCatabolic ProcessCell LineCell physiologyCellsCellular biologyChromatinChronicClinicalClustered Regularly Interspaced Short Palindromic RepeatsCrohn&aposs diseaseCytoplasmDNA ResequencingDataDepositionDiagnosisDiseaseDrug TargetingEthnic OriginEthnic PopulationEtiologyEuropeanEuropean ancestryFollow-Up StudiesGenderGenesGeneticGenetic HeterogeneityGenetic TranscriptionGenetic studyGenotypeGiftsHeritabilityHigh PrevalenceHispanic AmericansHispanic PopulationsHomeostasisHumanIGA GlomerulonephritisImmuneImmune System DiseasesIndividualInflammationInflammatoryInterventionKidneyKnowledgeLeadLifeLinkLinkage DisequilibriumLupusLupus NephritisLymphocyteLysosomesMapsMediatingMetabolic stressMinority GroupsMolecularMolecular Mechanisms of ActionMorbidity - disease rateMultiple SclerosisNephritisNucleic Acid Regulatory SequencesOrganOrganellesPathogenesisPathogenicityPathway interactionsPatientsPlayPopulation HeterogeneityPredispositionProcessProductionRegulationRegulatory ElementReportingResearchResourcesRiskRoleSamplingSignal TransductionSingle Nucleotide PolymorphismSkinStructureSusceptibility GeneSystemSystemic Lupus ErythematosusT-LymphocyteTargeted ResequencingTissuesTranslatingVariantWomanautoreactivitybase editingcausal variantchronic autoimmune diseaseclinical heterogeneitycurative treatmentsdisease phenotypeeffective therapyethnic diversityethnic minorityfollow-upgenome wide association studykidney cellknockout genemisfolded proteinmortalitymulti-ethnicmultiorgan damagenovelpathogenic autoantibodiespodocyteprotein degradationrare variantresponserisk variantsexsynergism
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Swapan K. Nath其他文献
Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.
白癜风的遗传流行病学:多位点隐性交叉验证。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:9.8
- 作者:
Swapan K. Nath;Partha P. Majumder;James J. Nordlund - 通讯作者:
James J. Nordlund
potential for generating B cells with a diverse immunoglobulin repertoire Human fetal, cord blood, and adult lymphocyte progenitors have similar
产生具有多种免疫球蛋白库的 B 细胞的潜力 人类胎儿、脐带血和成人淋巴细胞祖细胞具有相似的特性
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Grant R. Kolar;Takafumi Yokota;Maria Isabel D. Rossi;Swapan K. Nath;J. D. Capra - 通讯作者:
J. D. Capra
Swapan K. Nath的其他文献
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{{ truncateString('Swapan K. Nath', 18)}}的其他基金
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
- 批准号:
10618360 - 财政年份:2022
- 资助金额:
$ 75.26万 - 项目类别:
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
- 批准号:
10433444 - 财政年份:2022
- 资助金额:
$ 75.26万 - 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
- 批准号:
9895394 - 财政年份:2020
- 资助金额:
$ 75.26万 - 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
- 批准号:
10115587 - 财政年份:2020
- 资助金额:
$ 75.26万 - 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
- 批准号:
8995183 - 财政年份:2015
- 资助金额:
$ 75.26万 - 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
- 批准号:
8823171 - 财政年份:2015
- 资助金额:
$ 75.26万 - 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
- 批准号:
9259737 - 财政年份:2014
- 资助金额:
$ 75.26万 - 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
- 批准号:
8776043 - 财政年份:2014
- 资助金额:
$ 75.26万 - 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
- 批准号:
9053279 - 财政年份:2014
- 资助金额:
$ 75.26万 - 项目类别:
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