Transcription Factor Genetics in Lupus

狼疮的转录因子遗传学

基本信息

批准号：
10382388
负责人：
Leah Claire Kottyan
金额：
$ 44.79万
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/10382388
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 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

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.

抽象的系统性红斑狼疮（SLE 或狼疮）是一种无法治愈、使人衰弱的自身免疫性疾病，其特征是由于广泛的炎症和自身抗体的大量产生。遗传学无疑有助于 SLE 的病因学，统计上稳健的关联研究建立了 83 个独立的 SLE 遗传风险位点。然而，由于缺乏明确的机制见解，SLE 的有效诊断、治疗和预防受到阻碍深入了解这些遗传位点的生物学意义。 83 个独立 SLE 风险位点中的 21 个编码转录因子，约 90% 的 SLE 风险位点仅包含非编码变异。因此，基因调控可能是 SLE 遗传病因学的一个关键方面。因此，我们的目标是确定机械贡献 SLE 的转录因子。在我们的提案中，我们评估了风险对下游的直接生物影响改变转录因子氨基酸序列的变体（IRF7 - 目标 1），改变转录因子氨基酸序列的多种风险变体第二个转录因子（SPI1/PU.1 - 目标 2）的基因组结合位点，并检查协同控制这两种蛋白质的基因表达（目标 3）。我们还使用创新的新小鼠品系和实验狼疮模型探索这两个因素在疾病发病机制中的作用（目标 3）。在目标 1 中，我们努力确定干扰素调节因子 7 (IRF7) 412 位基因型的原因改变细胞对细胞内信号（包括来自 Toll 样受体的信号）的功能反应。这些数据将成为开发 Q412 特异性 IRF7 抑制剂作为新疗法的重要依据系统性红斑狼疮。在目标 2 中，我们基于转录因子 SPI1/PU.1 在 SLE 风险基因座处或附近结合的发现在许多细胞类型中，包括自然杀伤 (NK) 细胞，其数量超出了预期。全球最新数据将 NK 细胞功能障碍与狼疮风险联系起来，并支持新兴观点，即 NK 细胞代表了重要的新功能治疗干预的目标。我们利用我们的 NK 细胞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位点发生改变，导致表达失调 SLE 患者 NK 细胞中的靶基因。在目标 3 中，我们使用具有 SLE 风险的创新小鼠品系： IRF7 的相关变体或 PU.1 的 NK 细胞限制性缺陷，以确定这些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，其中这两个因子可以协同结合，调节基因表达，促进疾病。我们的提案利用了协作性、概念性和方法创新，在理解独立和独立的方面取得有意义的进展两种不同转录因子与 SLE 交叉的潜在组合分子机制促进疾病的风险位点。