The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation

项目总结 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，重点是免疫中性二型性的分子机制 精神错乱。为实现这一目标，职业发展计划将通过以下途径发展研究和专业技能 研究经验、临床沉浸、课程作业和额外的专业培训相结合 活动；都是在一个跨学科专家组的指导下进行的。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)炎症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；4)交流、合作、教学、写作和 额外的教员技能。 此外，研究项目的完成将为职业发展计划的制定奠定科学基础 为候选人未来的研究奠定基础。研究项目总结如下： 免疫疾病的表现形式上的性别差异代表了最显著和 男性和女性之间的生物差异的未解释的例子。许多自身免疫性疾病 女性患病率显著增加(例如系统性红斑狼疮[SLE]，女性对男性 比例为9：1)，而相比之下，感染传染病的男性比女性更多。 我们的初步结果表明，干扰素(干扰素)介导的免疫反应，宿主中的关键事件 在性激素非依赖性的人角质形成细胞中，防御和炎症表现出性别二型性 举止。一直以来，女性皮肤偏向于增加与以下相关基因的表达 自身免疫性疾病易感性。这些基因独立于性激素调节，并且 受VGLL3调控，VGLL3是一种女性增加的假定转录因子。VGLL3促进基因表达 免疫基因，包括干扰素刺激基因(ISGs)，其方式与 在包括狼疮在内的多种偏向女性的自身免疫性疾病中存在转录转录改变。 该项目旨在通过检测干扰素应答中的性二型性的分子基础。 假设女性体内较高水平的VGLL3能够启动ISGs对致敏干扰素的刺激 反应和/或延迟从刺激中恢复。为了解决这一问题，我们提出了以下具体目标： ·目的1.确定对IFN转录反应的性别差异以及VGLL3对其的调节 ·目的2.建立性别相关ISG图谱的染色质机制 ·目的3.确定VGLL3在体内调节干扰素介导的免疫过程中的作用 随着这项工作的成功完成，我们将在理解 性别依赖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、针对性别的治疗措施。

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.