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: 10532705
• 负责人: Yun Liang
• 金额: $ 0.81万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532705
• 关键词: Address; Affect; Agonist; Animal Model; Autoimmune Diseases; Autoimmunity; Biological; Chromatin; Chromatin Modeling; 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; 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; Viral; Withdrawal; Woman; Work; Writing; career; career development; 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，重点是免疫中性二态性的分子机制 疾病。为了实现这一目标，职业发展计划将通过 研究经验，临床沉浸，课程和其他专业培训的结合 活动;所有这些都是跨学科专家的心态。具体而言，它专注于培训： 1）皮肤感染的分子方面； 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）沟通，协作，教学，写作和 其他教师技能。 此外，职业发展计划中研究项目的完成将奠定科学 候选人未来研究的基础。研究项目总结如下： 免疫体现中的性别差异代表了最显着的和 男性和女性生物学差异的无法解释的例子。许多自身免疫性疾病 女性的患病率显着增加（例如，全身性红斑狼疮[SLE]，女性到男女 比率9：1），而相比之下，传染病比男女影响更多的男性。 我们的初步结果表明干扰素（IFN）介导的免疫调查，主机中的关键事件 防御和炎症，性激素独立的人角质形成细胞中暴露的性二态性 方式。一致地，雌性人皮肤偏向于增加基因的表达 自身免疫性疾病的敏感性。这些基因独立于性激素调节，并且是 由vgll3（一种女性提出的推定转录因子）调节。 vgll3促进了 免疫基因，包括干扰素刺激的基因（ISGS），与与之显着相关的方式 包括狼疮在内的多种女性偏见的自身免疫性疾病中存在转录组改变。 该项目旨在通过测试IFN反应中性别二态性的分子基础 假设女性中较高水平的VGLL3能够启动ISG朝着敏感的干扰素启动 反应和/或延迟从刺激中恢复。为了解决这个问题，我们提出以下具体目标： 目标1。确定对IFN的转录响应中的性别分布及其对VGLL的调节3 目标2。建立与性别依赖性ISG谱的染色质机制 目标3。确定VGLL3在控制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，我们将取得重大进步来理解 性别依赖性免疫过程的分子基础。这项工作也可能成为 新颖的，特定于性别的感染和自身免疫性疾病的措施。