Understanding the immunometabolic mechanism of VGLL3 mediating female-biased autoimmunity

摘要 自身免疫性疾病在女性中的患病率显著增加（如系统性红斑狼疮 [SLE]男女比例为9：1），而相比之下，传染病对男性的影响多于女性。 尽管其临床影响，性别偏见的免疫调节的分子基础仍然难以捉摸。到 为了弥补这一知识空白，本项目重点研究VGLL 3（Vestigial Like）的免疫代谢功能。 家族成员3），一种女性增加的角质形成细胞表达的分子，已知可促进皮肤和 系统性自身免疫该项目测试了VGLL 3协调女性偏好的代谢的假设， 应激反应，其过度激活通过以下方式引起自身免疫： 目标1。定义由VGLL 3介导的女性偏向的细胞应激反应。 目标2.确定代谢应激通过以下途径增强VGLL 3诱导的分子机制： 干扰素α 目标3。建立VGLL 3介导的应激反应在自身免疫发病机制中的体内作用。 随着所提出的工作的成功完成，我们将对分子基础有更深入的了解 免疫系统中潜在的两性异形通过建立VGLL 3的免疫代谢功能，我们将 证明了维持代谢稳态在对抗自身免疫中的重要性，并提供了一种 免疫相关疾病性别特异性预防和治疗的新靶点和途径。

ABSTRACT Autoimmune diseases exhibit 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. Despite its clinical impact, the molecular underpinnings of sex-biased immune regulation remain elusive. To address this knowledge gap, this project focuses on the immunometabolic function of VGLL3 (Vestigial Like Family Member 3), a female-increased, keratinocyte-expressed molecule known to promote both cutaneous and systemic autoimmunity. This project tests the hypothesis that VGLL3 coordinates female-biased metabolic stress response, whose hyperactivation causes autoimmunity by: Aim 1. Define the female-biased cellular stress response mediated by VGLL3. Aim 2. Determine the molecular mechanism by which metabolic stress potentiates VGLL3 induction by IFNα. Aim 3. Establish the in vivo role of VGLL3-mediated stress response in autoimmune pathogenesis. With successful completion of the work proposed, we will have gained insights into the molecular basis underlying sexual dimorphism in immunity. By establishing the immunometabolic function of VGLL3, we will demonstrate the importance of maintaining metabolic homeostasis in combating autoimmunity, and provide a novel target and pathway for sex-specific prevention and treatment of immune-associated diseases.