Understanding the immunometabolic mechanism of VGLL3 mediating female-biased autoimmunity

了解 VGLL3 介导女性偏向性自身免疫的免疫代谢机制

基本信息

批准号：
10356376
负责人：
Yun Liang
金额：
$ 21.61万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356376
关键词：
Address Affect Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity Binding Sites Cell Death Cells Cellular Stress Cellular Stress Response Chromatin Clinical Communicable Diseases Complex Cutaneous Data Dependence Deposition Disease EP300 gene Exhibits FOS gene Family member Feedback Female Genetic Epistasis Homeostasis Immune Immune System Diseases Immunity In Vitro Inflammatory Interferon-alpha Interferons Knowledge Lupus Malnutrition Measurement Mediating Metabolic Metabolic stress Molecular Monitor Mus Nutrient Nutritional Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Prevalence Prevention Regulation Role Sex Bias Signal Transduction Sjogren&apos s Syndrome Starvation Stress Systemic Lupus Erythematosus Systemic Scleroderma TP53 gene Testing Transcriptional Activation Up-Regulation Woman Work autoimmune pathogenesis base biological adaptation to stress chromatin immunoprecipitation cytokine disorder prevention experimental study high risk population immunoregulation in vivo insight interleukin-17C keratinocyte lupus-like male men novel nutrient deprivation overexpression personalized medicine promoter response sex sexual dimorphism systemic autoimmunity targeted treatment

项目摘要

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 IFN. 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.

抽象的自身免疫性疾病在女性中的患病率显着增加（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，传染病对男性的影响多于女性。尽管具有临床影响，但性别偏见免疫调节的分子基础仍然难以捉摸。为了解决这一知识差距，该项目重点关注 VGLL3（Vestigial Like 家庭成员 3)，一种女性增加的、角质形成细胞表达的分子，已知可促进皮肤和该项目测试了 VGLL3 协调女性偏向代谢的假设。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 VGLL3 介导的女性偏向的细胞应激反应。目标 2. 确定代谢应激增强 VGLL3 诱导的分子机制干扰素α。目标 3. 确定 VGLL3 介导的应激反应在自身免疫发病机制中的体内作用。随着所提出的工作的成功完成，我们将深入了解分子基础通过建立 VGLL3 的免疫代谢功能，我们将了解免疫中潜在的性别二态性。证明维持代谢稳态在对抗自身免疫方面的重要性，并提供性别特异性预防和治疗免疫相关疾病的新靶点和途径。