Lupus Association with Signal Transducer and Activator of Transcription 4

狼疮与信号转导器和转录激活器的关联 4

• 批准号: 8598799
• 负责人: John Barker Harley
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598799
• 关键词: African American; Alleles; Autoimmunity; Award; Binding; Biological; Cells; Chromosome Mapping; Crohn' s disease; Curcumin; DNA Methylation; DNA Sequence; Data; Diagnosis; Disease; Epigenetic Process; Etiology; Faculty; Gene Expression; Genes; Genetic; Genomics; Genotype; Haplotypes; Hispanics; Histones; Immune System Diseases; In Vitro; Inflammatory; Inflammatory Response; Informatics; Insulin-Dependent Diabetes Mellitus; Interferons; Intervention; Introns; Knowledge; Lentivirus Vector; Life; Linkage Disequilibrium; Literature; Lupus; Maps; Mediating; Messenger RNA; Methodology; Methods; MicroRNAs; Military Personnel; Minority; Mission; Modification; Molecular; Pathogenesis; Population; Production; Proteins; RNA analysis; Regulation; Research; Rheumatoid Arthritis; Risk; Role; STAT4 gene; STAT4 protein; Stimulus; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Variant; design; disorder risk; genetic risk factor; genetic variant; high risk; improved; inhibitor/antagonist; insight; new technology; novel; novel therapeutics; physical mapping; programs; public health relevance; research study; response; risk variant; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): Of the many genes recently discovered to be associated with Systemic Lupus Erythematosus the haplotype in STAT4 is among the most powerful outside the HLA region. STAT4 is an important inflammatory transcription factor with the level in the cell determining the magnitude of the response to the genes that STAT4 controls. This association is curious because it is localized in the fourth intron and the biological relevance of the relationship of this piece of DN to the function or activity of STAT4 is poorly understood. Our preliminary together with recent literature show that the risk allele expresses a higher level of STAT4 mRNA and protein and leads to increased sensitivity to Interferon-¿ (IFN-¿). The variant causing the association with lupus in STAT4 is located in a 55.5kb haplotype. DNA sequencing has defined many differences between the risk and non-risk haplotype. We will incorporate new genotyping and DNA sequencing data available and now being generated into a complete map, defining the genomic boundaries containing the causal variant(s) and identifying all of the possible variants that could contribute to disease risk and reducing the interval (Aim 1). Next, since disease risk appears to be related to expression, we will explore sequence specific epigenetic alterations in histone marks and DNA methylation to identify the regions of the risk haplotype that are poised for increased STAT4 mRNA production (Aim 2). This will be a novel application of epigenetics for allele specific gene mapping and candidate causal variant identification that if successful will have general application for identifying gene variants that change disease risk by changing expression level. We will evaluate the hypothesis that the differential binding of transcription factors are responsible for the difference in STAT4 gene expression with informatic approaches to identify potential risk haplotype differences controlling gene expression and by applying in vitro methods to establish which of the identified variants is actually responsible for the change in gene expression (Aim 3). We anticipate identifying the causal variant in STAT4 and explaining some of the important details of the mechanism that generates risk for lupus. Finally, throughout the proposed program of research on STAT4 we will explore progressively more sophisticated strategies for decreasing the increased STAT4 activity in the risk haplotype (Aim 4). Initially, we will explore the potential impact on STAT4 activity with the known inhibitors (lisopfylline, curcumin, and statins). Later in the program and after we identify candidate causal transcription factors, we will deliver specific shRNA with lentivirus vectors to inhibit the actionof the candidate causal transcription factor(s), which may have the potential to reduce the increased STAT4 expression of the risk allele, returning the level of expression of the risk haplotype close to the STAT4 expression of the non-risk allele and, thereby, reducing the risk of lupus. STAT4 also is associated with rheumatoid arthritis, Crohn's disease, and type 1 diabetes, giving broad importance to any effort to understand STAT4 mechanism in autoimmunity, especially if this knowledge were to bring us closer to more effective and specific therapies for the immune dysfunction of these diseases.

描述（由申请人提供）： 在最近发现与全身性红斑狼疮有关的许多基因中，STAT4中的单倍型是HLA地区以外最强大的。 STAT4是重要的炎症转录因子，细胞中的水平决定了大小 对STAT4控制的基因的响应。这种关联很好奇，因为它位于第四个内含子中，并且该DN与STAT4功能或活动的关系的生物学相关性知之甚少。我们的初步文献以及最近的文献表明，风险等位基因表达了更高水平的STAT4 mRNA和蛋白质，并导致对干扰素 - （IFN-€）的敏感性提高。在STAT4中引起与狼疮关联的变体位于55.5kb的单倍型中。 DNA测序定义了风险和非风险单倍型之间的许多差异。我们将合并新的基因分型和DNA测序数据，现在被生成完整的地图，定义包含因果变体的基因组边界，并识别所有可能的变体 导致疾病风险并减少间隔（目标1）。接下来，由于疾病的风险似乎与表达有关，我们将探索组蛋白标记和DNA甲基化序列特定的表观遗传改变，以识别毒性单倍型的区域，这些区域被中毒以增加STAT4 mRNA的产生（AIM 2）。这将是表观遗传学特异性基因映射和候选因果变体鉴定的新型应用，如果成功将有一般应用来识别通过改变表达水平来改变疾病风险的基因变异。我们将评估以下假设：转录因子的差异结合是通过信息性的方法造成STAT4基因表达的差异，以鉴定控制基因表达的潜在风险单倍型差异，并应用体外方法来确定哪些已鉴定的变体实际上是导致基因表达变化的原因（AIM 3）。我们预计确定STAT4中的因果变体，并解释产生狼疮风险的机制的一些重要细节。最后，在拟议的有关STAT4的研究计划中，我们将逐步探索更复杂的策略，以减少风险单倍型中的STAT4活动增加（AIM 4）。最初，我们将使用已知的抑制剂（Lisopfylline，Curcumin和ptatins）探索对STAT4活性的潜在影响。 Later in the program and after we identify candidate causal transcription factors, we will deliver specific shRNA with lentivirus vectors to inhibit the action of the candidate causal transcription factor(s), which may have the potential to reduce the increased STAT4 expression of the risk allele, returning the level of expression of the risk haplotype close to the STAT4 expression of the non-risk allele and, thereby, reducing the risk of lupus. STAT4还与类风湿关节炎，克罗恩病和1型糖尿病有关，这对了解自身免疫性的STAT4机制的任何努力都广为人知，尤其是如果这些知识使我们更接近更有效，更特定的这些疾病免疫功能障碍。