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

项目摘要 自身免疫性疾病的特征是免疫系统功能障碍，其中身体攻击自身组织。 根据NIH的估计，自身免疫性疾病影响7.5%的美国人口，并且是主要的疾病之一。 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其患病率增加 据估计，总体而言，78%的受影响者是妇女。了解原因 女性对自身免疫性疾病的易感性是预防性疾病发展的基础。 在高风险人群中的措施，并可能导致新的治疗方法的个人与 建立疾病。 通过全基因组转录组分析，我们已经确定了一个女性偏向的分子标记 与广泛的性别依赖性共表达网络相关，并与自身免疫性疾病相关 易感性这种信号不受生物学年龄和性激素调节的影响， 转录因子VGLL 3，其具有显著的雌性偏向性表达。在全基因组水平上， VGLL 3靶基因与多种自身免疫性疾病密切相关，包括狼疮， 硬皮病，并且与免疫过程包括皮肤狼疮具有显著的转录组重叠， 这表明VGLL 3与自身免疫中的炎症反应紧密整合， 自身免疫过程的调节器。 基于这些发现，我们提出的中心假设是VGLL 3是一种表观遗传调节的蛋白质， 在促进自身免疫特异性炎症反应中具有关键作用的转录因子。这 该提案有可能通过增加我们的研究来显着推进自身免疫研究领域。 了解一种新的性别偏见的自身免疫性炎症通路， 确定这一途径的上游调控因子，并确定VGLL 3介导的机制 自身免疫反应鉴于狼疮中的强烈女性偏倚，SLE将用作研究的模型疾病 并通过我们的诊所和合作研究者轻松获取患者样本。随着成功完成 根据所提出的工作，我们将在理解VGLL 3参与 促进SLE的自身免疫反应和疾病活动。此外，我们将提供一个坚实的基础， 开发新的预防和治疗措施，可能对 一系列自身免疫性疾病

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.