Role of the gender biased transcription factor VGLL3 in promoting autoimmune responses in SLE

性别偏向转录因子 VGLL3 在促进 SLE 自身免疫反应中的作用

• 批准号: 10112808
• 负责人: Johann Eli Gudjonsson
• 金额: $ 38.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112808
• 关键词: Address; Affect; Age; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological; Biology; Cause of Death; Cell Nucleus; Cells; ChIP-seq; Clinic; DNA; Data; Dendritic Cells; Development; Disease; Disease model; Disease susceptibility; Epigenetic Process; Event; Female; Foundations; Gene Expression; Genes; Genetic Transcription; Gonadal Steroid Hormones; Heart Diseases; Histones; Human Genome; Immune; Immune System Diseases; Immune system; Immunosuppressive Agents; Individual; Inflammatory; Inflammatory Response; Lead; Link; Lupus; Malignant Neoplasms; Measures; Mediating; Methylation; Modification; Molecular Profiling; Nuclear; Nuclear Translocation; Onset of illness; Organ; Pathway interactions; Patients; Play; Population; Predisposition; Prevalence; Preventive; Preventive measure; Process; Promoter Regions; Regulation; Regulatory Element; Research; Research Personnel; Role; Sampling; Scleroderma; Sex Bias; Solid; Specificity; Stimulus; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transcriptional Activation; United States National Institutes of Health; Widespread Disease; Woman; Work; base; cell type; disability; epigenetic silencing; gene repression; genome-wide; high risk population; histone modification; hormone regulation; keratinocyte; lupus cutaneous; male; men; monocyte; novel; novel strategies; novel therapeutic intervention; promoter; sex; side effect; transcription factor; transcriptomics

PROJECT SUMMARY Autoimmune diseases feature a dysfunction of the immune system in which the body attacks its own tissues. By NIH estimations, autoimmune diseases affect 7.5% of the U.S. population, and are among the leading causes of death and disability. A striking feature of many autoimmune diseases is their increased prevalence in females, and overall it is estimated that 78% of individuals affected are women. Understanding the cause of female-biased susceptibility to autoimmune diseases is fundamental to the development of preventative measures in high-risk populations, and may lead to novel therapeutic approaches for individuals with established disease. Through genome-wide transcriptomic analyses we have identified a female-biased molecular signature linked to extensive sex-dependent, co-expression networks and associated with autoimmune disease susceptibility. This signature was independent of biological age and sex-hormone regulation, and regulated by the transcription factor VGLL3, which had a prominent female biased expression. On a genome-wide level, VGLL3 target genes were strongly associated with multiple autoimmune diseases including lupus and scleroderma, and had a prominent transcriptomic overlap with immune processes including cutaneous lupus, suggesting that VGLL3 is tightly integrated with inflammatory responses in autoimmunity, and an upstream regulator of autoimmune processes. The central hypothesis of our proposal, based on these findings, is that VGLL3 is an epigenetically regulated transcription factor that has critical roles in promoting autoimmune specific inflammatory responses. This proposal has the potential to significantly advance the field of autoimmune research by increasing our understanding of a novel sex hormone-independent inflammatory pathway in gender biased autoimmunity, identify upstream regulators of this pathway, and determine the mechanisms by which VGLL3 mediates autoimmune responses. SLE will be used as the model disease for study given the strong female bias in lupus and easy access to patient samples through our clinics and co-investigators. With the successful conclusion of the work proposed, we will have taken major strides towards understanding the involvement of VGLL3 in promoting autoimmune responses and disease activity in SLE. In addition, we will provide a solid foundation towards development of novel preventive and therapeutic measures that may have major implications against a wide range of autoimmune diseases.

项目总结 自身免疫性疾病的特征是免疫系统功能障碍，身体攻击自己的组织。 据美国国立卫生研究院估计，自身免疫性疾病影响了7.5%的美国人口，是主要的 死亡和残疾的原因。许多自身免疫性疾病的一个显著特征是患病率增加。 在女性中，总体上估计78%的受影响个人是妇女。了解原因 女性对自身免疫性疾病的易感性是预防疾病发展的基础 在高危人群中采取措施，并可能导致对患有 已确定的疾病。 通过全基因组转录分析，我们已经确定了一个偏向女性的分子签名 与广泛的性别依赖、共表达网络有关，并与自身免疫性疾病有关 敏感度。这一信号与生物年龄和性激素调节无关，并受 转录因子VGLL3，有明显的女性偏向表达。在全基因组水平上， VGLL3靶基因与多种自身免疫性疾病包括狼疮和 硬皮病，与包括皮肤红斑狼疮在内的免疫过程有显著的转录重叠， 提示VGLL3在自身免疫中与炎症反应紧密结合，并在上游 自身免疫过程的调节者。 基于这些发现，我们建议的中心假设是VGLL3是一种受表观遗传调控的 在促进自身免疫特异性炎症反应中起关键作用的转录因子。这 该提案有可能显著推进自身免疫研究领域，通过增加我们的 性别偏向自身免疫中一种新的性激素非依赖性炎症途径的理解 确定这一途径的上游调节因子，并确定VGLL3介导的机制 自身免疫反应。鉴于狼疮中女性的强烈偏见，SLE将被用作研究的模型疾病 并通过我们的诊所和合作调查人员轻松获取患者样本。随着胜利的结束 提出的工作，我们将在理解VGLL3在 促进系统性红斑狼疮的自身免疫反应和疾病活动性。此外，我们还将提供坚实的基础 发展新的预防和治疗措施，这些措施可能对 范围广泛的自身免疫性疾病。