The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation

项目摘要 候选人的长期职业目标是成为免疫领域的独立调查员。 相关疾病，重点是免疫系统中性二态性的分子机制。 紊乱为实现这一目标，职业发展计划将通过以下方式发展研究和专业技能： 结合研究经验，临床沉浸，课程和额外的专业培训 活动;所有这些活动都在一个跨学科专家组的指导下进行。具体而言，它侧重于以下方面的培训： 1)皮肤炎症的分子方面; 2）炎性和自身免疫性疾病的动物模型; 3)自身免疫性疾病的临床方面;和4）沟通，协作，教学，写作，和 额外的教师技能。 此外，研究项目的完成将为职业发展规划奠定科学的基础。 为候选人未来的研究打下基础。研究项目概述如下： 免疫性疾病表现的性别差异是最显著和最重要的疾病之一。 无法解释的男女之间生物差异的例子。许多自身免疫性疾病 特征是女性患病率显著增加（如系统性红斑狼疮[SLE]，女性对男性 比例为9：1），而相比之下，传染病对男性的影响多于女性。 我们的初步结果表明，干扰素（IFN）介导的免疫反应，在宿主中的关键事件， 防御和炎症，在人类角质形成细胞中以不依赖性激素的方式表现出性二态性。 方式一致地，女性人类皮肤偏向于增加与以下相关的基因的表达： 自身免疫性疾病易感性这些基因独立于性激素调节， 由VGLL 3调节，VGLL 3是一种雌性增加的假定转录因子。VGLL 3促进以下基因的表达： 免疫基因，包括干扰素刺激基因（ISG），以一种与 转录组学改变存在于多种女性偏好的自身免疫性疾病，包括狼疮。 该项目旨在通过检测IFN应答中的性别二态性来确定其分子基础。 女性中较高水平的VGLL 3能够使ISG对致敏干扰素启动的假设 反应和/或从刺激延迟恢复。为解决这一问题，我们提出以下具体目标： ·目标1。确定对IFN的转录反应的性别差异及其通过VGLL 3的调节 ·目标2。建立性别依赖性ISG谱的染色质机制 目标3。确定VGLL 3在调节IFN介导的免疫过程中的体内作用 随着这项工作的顺利完成，我们将在理解 性别依赖性免疫过程的分子基础这项工作也可能成为 针对传染病和自身免疫性疾病的新的、性别特异性的治疗措施。

PROJECT SUMMARY The candidate's long-term career goal is to become an independent investigator in the field of immune- associated diseases, with a focus on molecular mechanisms underlying sexual dimorphisms in immune disorders. Towards this goal, the career development plan will develop research and professional skills through a combination of research experience, clinical immersion, coursework, and additional professional training activities; all under the mentorship of an interdisciplinary group of experts. Specifically, it focuses on training in: 1) molecular aspects of cutaneous inflammation; 2) animal models for inflammatory and autoimmune diseases; 3) clinical aspects of autoimmune diseases; and 4) communication, collaboration, teaching, writing, and additional faculty skills. In addition, the completion of the research project in the career development plan will lay the scientific groundwork for the candidate's future research. The research project is summarized below: Sex disparity in the manifestation of immune diseases represents one of the most remarkable and unexplained examples of the biological differences between men and women. Many autoimmune diseases feature strikingly increased prevalence in females (e.g. systemic lupus erythematosus[SLE], female-to-male ratio 9:1), whereas in contrast, infectious diseases affect more men than women. Our preliminary results suggest that interferon(IFN)-mediated immune responses, key events in host defense and inflammation, exhibit sexual dimorphisms in human keratinocytes in a sex-hormone independent manner. Consistently, the female human skin is biased towards increased expression of genes associated with autoimmune disease susceptibility. These genes are independent of sex-hormone regulation, and are regulated by VGLL3, a female-increased, putative transcription factor. VGLL3 promotes the expression of immune genes, including interferon-stimulated genes (ISGs), in a manner that is significantly associated with transcriptomic alterations present in multiple female-biased autoimmune diseases including lupus. This project aims to identify the molecular basis of sex dimorphisms in IFN responses by testing the hypothesis that higher levels of VGLL3 in females enable priming of ISGs towards sensitized interferon responses and/or delayed recovery from stimulation. To address this we propose the following specific aims: · Aim 1. Determine sex disparities in transcriptional responses to IFNs and their regulation by VGLL3 · Aim 2. Establish the chromatin mechanism for sex-dependent ISG profiles · Aim 3. Determine the in vivo role of VGLL3 in regulating IFN-mediated immune processes With the successful completion of this work, we will have made major advances towards understanding of the molecular basis for sex-dependent immunological processes. This work may also become the basis for novel, sex-specific therapeutic measures for infectious and autoimmune diseases.