The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation

VGLL3 在性二态性干扰素驱动的炎症中的作用

• 批准号: 10311525
• 负责人: Yun Liang
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311525
• 关键词: Address; Affect; Agonist; Animal Model; Autoimmune Diseases; Autoimmunity; Biological; Chromatin; Clinical; Clinical Research; Collaborations; Communicable Diseases; Communication; Complex; Cutaneous; Dendritic Cells; Development; Development Plans; Disease; Disease susceptibility; Educational process of instructing; Event; Exhibits; Faculty; Family member; Female; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Histones; Host Defense; Human; Immersion; Immune; Immune System Diseases; Immune response; Immunologics; In Vitro; Inflammation; Inflammatory; Interferon Activation; Interferon Type II; Interferon-alpha; Interferons; Kinetics; Light; Lupus; Measures; Mediating; Mentorship; Modeling; Molecular; Molecular Profiling; Mus; Nature; Pathway interactions; Pharmaceutical Preparations; Prevalence; Prevention; Preventive measure; Process; Recovery; Regulation; Research; Research Personnel; Research Project Grants; Resistance; Role; Severities; Sex Bias; Sex Differences; Shapes; Skin; Skin injury; Systemic Lupus Erythematosus; TLR7 gene; Testing; Therapeutic; Training; Training Activity; Transcript; Ultraviolet B Radiation; Withdrawal; Woman; Work; Writing; base; career; career development; chromatin remodeling; design; experience; histone modification; hormone regulation; human female; immunoregulation; in vivo; irradiation; keratinocyte; male; men; non-histone protein; novel; overexpression; personalized medicine; personalized therapeutic; programs; recruit; response; sex; sex disparity; sexual dimorphism; skills; systemic autoimmunity; transcription factor; transcriptomics

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.

项目概要 候选人的长期职业目标是成为免疫领域的独立研究者 相关疾病，重点关注免疫性别二态性背后的分子机制 为了实现这一目标，职业发展计划将通过发展研究和专业技能。 研究经验、临床沉浸、课程作业和额外专业培训的结合 活动；所有这些都在跨学科专家小组的指导下进行。具体来说，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；以及 4) 沟通、协作、教学、写作和 额外的教师技能。 此外，职业发展规划中研究项目的完成，将为职业发展规划的科学性奠定基础。 该研究项目总结如下： 免疫疾病表现中的性别差异是最显着和最重要的问题之一。 许多无法解释的男性和女性之间的生物学差异的例子。 女性患病率显着增加（例如系统性红斑狼疮 [SLE]、女性比男性 比例 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）介导的免疫反应是宿主体内的关键事件 防御和炎症，在不依赖性激素的情况下，人类角质形成细胞表现出性别二态性 一致地，女性人类皮肤倾向于增加与相关基因的表达。 自身免疫性疾病的易感性这些基因与性激素调节无关。 受 VGLL3 调节，VGLL3 是一种女性增加的假定转录因子。 免疫基因，包括干扰素刺激基因（ISG），其方式与 转录组改变存在于包括狼疮在内的多种女性自身免疫性疾病中。 该项目旨在通过测试 IFN 反应中性别二态性的分子基础 假设女性体内较高水平的 VGLL3 能够启动 ISG 对敏化干扰素的作用 为了解决这个问题，我们提出了以下具体目标： · 目标 1. 确定 IFN 转录反应的性别差异及其受 VGLL3 的调节 · 目标 2. 建立性别依赖性 ISG 图谱的染色质机制 · 目标 3. 确定 VGLL3 在调节 IFN 介导的免疫过程中的体内作用 随着这项工作的成功完成，我们将在理解 这项工作也可能成为性别依赖性免疫过程的分子基础。 针对传染病和自身免疫性疾病的新颖的、针对性别的治疗措施。