The role of high endothelial venules in sex dimorphism in rheumatoid arthritis

高内皮微静脉在类风湿性关节炎性别二态性中的作用

基本信息

批准号：
10739128
负责人：
Junko Sawada
金额：
$ 40.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739128
关键词：
Address Alleles Animal Model Autoimmune Diseases Blood Vessels Cells Chronic Chronic Childhood Arthritis Chronic Obstructive Pulmonary Disease Compensation Complex Data Degenerative polyarthritis Development Disease Disease Progression Dose Embryonic Development Endothelium Exhibits Female Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genotype-Tissue Expression Project Gonadal Steroid Hormones High Endothelial Venule Hormonal Hormones Human Immune Immunity Immunize Inflammation Inflammatory Investigation Knowledge Leukocytes Link Lung infections Lupus Lymphocyte Malignant Neoplasms Membrane Modeling Multiple Sclerosis Mus Outcome Study Parabiosis Patient-Focused Outcomes Physical Function Play Predisposition Prevalence Proteins Quality of life RNA Reaction Regulation Research Rheumatoid Arthritis Role Sex Bias Sex Differences Single Nucleotide Polymorphism Sjogren&apos s Syndrome Symptoms Synovial Membrane Synovial joint Therapeutic Tissues Tuberculosis Untranslated RNA Up-Regulation Woman X Chromosome X Inactivation adaptive immunity arthropathies autoreactivity cell type early onset joint injury male migration mouse model recruit secondary lymphoid organ sexual dimorphism tertiary lymphoid organ

项目摘要

Summary/Abstract: The proposed study addresses the mechanisms of sex differences in rheumatoid arthritis; in particular, we focus on the high endothelial venules and their roles in female-biased disease development. Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide, and it is a chronic, complex, and heterogeneous autoimmune disease. The treatment mainly focuses on suppressing excess inflammation and slowing the disease progression to minimize joint damage and enhance physical function and quality of life. There's no cure for rheumatoid arthritis. The complex abnormal regulation of immunity causes auto-reactive inflammatory reactions, leading to persistent inflammation and articular destruction. RA is a well- known female-biased disease (3:1 ratio). Women have higher susceptibility, earlier onset, severer symptoms, and more exacerbated disease progression. Interestingly, juvenile idiopathic arthritis which sex hormones are negligible, also shows a female-biased disease prevalence, illuminating the genetic predispositions in rheumatoid arthritis in females. The majority of research focuses on the hormonal influences and dysregulation of immune cells caused by genetic disposition. Yet, the contribution of the tissue microenvironment to sex differences has remained elusive. In particular, blood vessels are the most critical gateway for the leukocytes to migrate into the joint synovial membrane. Research on the blood vessels will uncover the unknown mechanism for the disease development and female biases in RA. This project will focus on ectopic high endothelial venules (HEVs), specialized vessels for leukocyte recruitment which have been found in RA but not in osteoarthritis. HEVs play a critical role in the initiation of adaptive immunity in secondary lymphoid organs by recruiting naïve leukocytes. Previous single-cell data of HEVs shows the potential skewed X-inactivation and upregulation of X-linked genes. As a result of dose compensation at embryonic development, one X-chromosome in females is silenced. However, 15-23% of X- linked human genes escape from this X-inactivation, causing upregulation of X-linked genes. We will take two independent approaches to investigate if HEVs and their skewed X-inactivation are the major cause of sex bias in RA. Aim 1: To identify the skewed X-inactivation and upregulation of X-linked genes in HEVs in human RA. Aim 2: To perform a proof-of-concept study in animal models to demonstrate the cause of sex dimorphisms. This proposed project initiates investigating the X-linked genes in HEVs and seeking their potential impact on female-biased RA progression. The studies will also uncover the X-inactivation and bi-allelic gene expression in ectopic HEVs. Our new mouse models to perform a proof-of-concept study are useful for future investigation to examine the significance of skewed X-inactivation in non-circulating local tissues for sexual dimorphisms in RA.

摘要/摘要：拟议的研究特别关注类风湿性关节炎的性别差异机制；关于高内皮微静脉及其在女性偏向疾病发展中的作用。类风湿性关节炎 (RA) 是世界范围内最常见的炎症性关节病，是一种慢性、复杂且异质的自身免疫性疾病，治疗主要集中在抑制过度的治疗。炎症并减缓疾病进展，以最大限度地减少关节损伤并增强身体功能和类风湿性关节炎是由复杂的免疫调节异常引起的。自身反应性炎症反应，导致持续性炎症和关节破坏。已知女性偏向的疾病（3：1的比例）女性具有更高的易感性，发病更早，症状更严重，性激素会加剧疾病进展。可以忽略不计，也显示出女性偏向的疾病患病率，阐明了遗传易感性女性类风湿性关节炎的大部分研究集中在荷尔蒙的影响和失调上。然而，组织微环境对性别的影响。差异仍然难以捉摸，特别是血管是白细胞进入的最关键的门户。对血管的研究将揭示未知的机制。 RA 的疾病发展和女性偏见。该项目将重点关注异位高内皮微静脉 (HEV)，即白细胞的专用血管已在 RA 中发现但在 HEV 中未发现的募集在引发中发挥着关键作用。通过招募幼稚白细胞来实现次级淋巴器官的适应性免疫。 HEV 显示出由于剂量的影响，X 连锁基因可能出现偏态失活和上调。在胚胎发育过程中，女性的一条 X 染色体被沉默，但 15-23% 的 X 染色体被沉默。连锁的人类基因逃脱了这种 X 连锁失活，导致 X 连锁基因的上调。我们将采取两个。独立的方法来调查 HEV 及其倾斜的 X 失活是否是性别偏见的主要原因目标 1：确定人类 RA 中 HEV 中 X 连锁基因的倾斜 X 失活和上调。目标 2：在动物模型中进行概念验证研究，以证明性别二态性的原因。该拟议项目启动调查 HEV 中的 X 连锁基因并寻求其潜在影响这些研究还将揭示 X 失活和双等位基因表达。我们用于进行概念验证研究的新小鼠模型对于未来的研究很有用。检查非循环局部组织中偏向的 X 失活对于性别二态性的重要性 R.A.