Transcription Factor Genetics in Lupus

狼疮的转录因子遗传学

基本信息

批准号：
9894767
负责人：
Leah Claire Kottyan
金额：
$ 44.85万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894767
关键词：
Alleles Amino Acid Sequence Amino Acids Arginine Autoantibodies Autoimmune Diseases Binding Binding Sites Biological Cell Line Cell physiology Cells Clinical Code DNA Binding Data Data Set Development Diagnosis Dimerization Disease Elements Enhancers Etiology Exhibits Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genetic Variation Genome Genomics Genotype Glutamine Human Immune Immune System Diseases Immunologics Inflammation Inflammatory Interferon Type I Interferons Investigation Leukocytes Link Lupus Lymphocyte Lymphocyte Function Mediating Methodology Modeling Molecular Mouse Strains Mus Natural Killer Cells Nature Nuclear Nuclear Translocation Nucleic Acid Regulatory Sequences Pathogenesis Pathogenicity Patients Positioning Attribute Prevention Production Proteins Risk Role SPI1 gene Signal Transduction Stimulus Systemic Lupus Erythematosus Testing Therapeutic Intervention Toll-like receptors Transactivation Transcriptional Regulation Untranslated RNA Variant Work bioinformatics tool cell type chromatin immunoprecipitation clinical practice clinically relevant combinatorial cytokine disorder risk genetic risk factor genetic variant genome editing genomic locus inhibitor/antagonist innovation insight interferon regulatory factor-7 lupus-like mouse model new therapeutic target novel therapeutics public health relevance response risk variant targeted treatment tool transcription factor

Alleles Amino Acid Sequence Amino Acids Arginine Autoantibodies Autoimmune Diseases Binding Binding Sites Biological Cell Line Cell physiology Cells Clinical Code DNA Binding Data Data Set Development Diagnosis Dimerization Disease Elements Enhancers Etiology Exhibits Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genetic Variation Genome Genomics Genotype Glutamine Human Immune Immune System Diseases Immunologics Inflammation Inflammatory Interferon Type I Interferons Investigation Leukocytes Link Lupus Lymphocyte Lymphocyte Function Mediating Methodology Modeling Molecular Mouse Strains Mus Natural Killer Cells Nature Nuclear Nuclear Translocation Nucleic Acid Regulatory Sequences Pathogenesis Pathogenicity Patients Positioning Attribute Prevention Production Proteins Risk Role SPI1 gene Signal Transduction Stimulus Systemic Lupus Erythematosus Testing Therapeutic Intervention Toll-like receptors Transactivation Transcriptional Regulation Untranslated RNA Variant Work bioinformatics tool cell type chromatin immunoprecipitation clinical practice clinically relevant combinatorial cytokine disorder risk genetic risk factor genetic variant genome editing genomic locus inhibitor/antagonist innovation insight interferon regulatory factor-7 lupus-like mouse model new therapeutic target novel therapeutics public health relevance response risk variant targeted treatment tool transcription factor

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项目摘要

ABSTRACT Systemic Lupus Erythematosus (SLE or lupus) is an incurable, debilitating autoimmune disease characterized by widespread inflammation and rampant production of autoantibodies. Genetics undoubtedly contributes to the etiology of SLE, with statistically robust association studies establishing 83 independent SLE genetic risk loci. Yet, effective diagnosis, treatment, and prevention of SLE is hindered by a dearth of clear mechanistic insights into the biological significance of these genetic loci. Twenty-one of 83 independent SLE risk loci encode transcription factors, and ~90% of SLE risk loci only contain variants that are non-coding. Thus, gene regulation is a likely critical aspect of SLE genetic etiology. We therefore aim to determine the mechanistic contributions of transcription factors to SLE. In our proposal, we assess the immediate downstream biological impact of risk variants that alter the amino acid sequence of a transcription factor (IRF7 - Aim 1), multiple risk variants that alter the genomic binding sites of a second transcription factor (SPI1/PU.1 - Aim 2), and examine cooperative control of gene expression by these two proteins (Aim 3). We also use innovative new mouse strains and experimental lupus models to explore the role of both factors in disease pathogenesis (Aim 3). In Aim 1, we endeavor to identify why the genotype at position 412 in interferon regulatory factor-7 (IRF7) changes the functional response of cells to intracellular signals, including those from toll-like receptors. These data will be important rationale for the development of Q412-specific inhibitors of IRF7 as novel therapeutics in SLE. In Aim 2, we build on our finding that the transcription factor SPI1/PU.1 binds at or near SLE risk loci much more than expected by chance in numerous cell types, including natural killer (NK) cells. Recent data globally link NK cell dysfunction to lupus risk, and support the burgeoning view that NK cells represent important new targets for therapeutic interventions. We leverage our NK cell expertise and these exciting new data to test the hypothesis that PU.1 binding is altered at multiple lupus genetic risk loci, leading to dysregulated expression of target genes in NK cells from SLE patients. In Aim 3, we use innovative mouse strains harboring an SLE risk- associated variant of IRF7 or NK-cell-restricted deficiency of PU.1 to determine the pathogenic roles of these transcription factors in the development of lupus. We also examine molecular interaction of PU.1 and IRF7 at composite DNA binding elements in the genome of NK cells, where these two factors may cooperatively bind, regulate gene expression, and promote disease. Our proposal leverages collaborative, conceptual, and methodological innovation to make meaningful progress towards the understanding of the independent and potentially combinatorial molecular mechanisms by which two different transcription factors intersect with SLE risk loci to promote disease.

抽象的全身性红斑狼疮（SLE或狼疮）是一种无法治愈的，令人衰弱的自身免疫性疾病通过广泛的炎症和自身抗体的猖ramp产生。遗传学无疑有助于 SLE的病因，具有统计坚固的关联研究，建立了83个独立的SLE遗传风险基因座。然而，有效的诊断，治疗和预防SLE受到明显的机械见解的限制这些遗传基因座的生物学意义。 83个独立SLE风险基因座编码中的21个转录因子，〜90％的SLE风险基因座仅包含非编码的变体。因此，基因调节是SLE遗传病因的可能关键方面。因此，我们旨在确定转录因子到SLE。在我们的提案中，我们评估了风险的直接下游生物学影响改变转录因子的氨基酸序列（IRF7 -AIM 1）的变体，多种风险变体会改变第二转录因子的基因组结合位点（SPI1/PU.1 -AIM 2），并检查合作控制这两种蛋白质的基因表达（AIM 3）。我们还使用创新的新老鼠菌株和实验性狼疮模型探索这两个因素在疾病发病机理中的作用（AIM 3）。在AIM 1中，我们努力确定为什么在干扰素调节因子-7（IRF7）中位置412的基因型为何改变细胞对细胞内信号的功能反应，包括来自Toll样受体的功能反应。这些数据对于开发IRF7的Q412特异性抑制剂作为新型治疗剂的发展将是重要的。 sle。在AIM 2中，我们建立在发现转录因子SPI1/PU.1在SLE风险基因座或接近SLE的发现的基础上在包括天然杀手（NK）细胞在内的许多细胞类型中，偶然的偶然性超出了预期。全球最新数据将NK细胞功能障碍与狼疮风险联系起来，并支持NK细胞代表重要新的新兴观点治疗干预措施的目标。我们利用我们的NK单元专业知识和这些令人兴奋的新数据来测试假设PU.1结合在多个狼疮遗传风险基因座上改变，导致表达失调来自SLE患者的NK细胞中的靶基因。在AIM 3中，我们使用具有SLE风险的创新小鼠菌株 - IRF7或NK细胞限制的PU.1的相关变体，以确定这些病的致病作用狼疮发展中的转录因子。我们还检查了pu.1和irf7的分子相互作用 NK细胞基因组中的复合DNA结合元件，这两个因素可能在其中结合，调节基因表达并促进疾病。我们的建议利用协作，概念和方法上的创新是为了理解独立和的有意义的进步潜在的组合分子机制，通过这种机制，两个不同的转录因子与SLE相交风险促进疾病的基因座。