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(例如系统性红斑狼疮 [SLE]，女性与男性的比例为9：1)，而相比之下，传染病影响的男性多于女性。 尽管有临床影响，但性别偏见免疫调控的分子基础仍然难以捉摸。至 为了解决这一知识差距，本项目重点研究VGLL3(残留样蛋白)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，已知促进皮肤和 全身性自身免疫。该项目测试了VGLL3协调女性偏向新陈代谢的假设 应激反应，其过度激活通过以下方式引起自身免疫： 目的1.明确VGLL3介导的偏向女性的细胞应激反应。 目的2.确定代谢应激增强VGLL3诱导的分子机制。 干扰素α。 目的3.探讨VGLL3介导的应激反应在自身免疫发病机制中的体内作用。 随着拟议工作的成功完成，我们将对分子基础有了更深入的了解 免疫中潜在的性别二型性。通过建立VGLL3的免疫代谢功能，我们将 证明维持代谢动态平衡在对抗自身免疫中的重要性，并提供 免疫相关疾病性别特异性防治的新靶点和新途径。

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.