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Unraveling the role of HLA-B51/ERAP1 in Behcet's eye disease

揭示 HLA-B51/ERAP1 在白塞氏眼病中的作用

基本信息

批准号：
10534165
负责人：
Johannes Nowatzky
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534165
关键词：
Affect Age Aminopeptidase Ankylosing spondylitis Antigen Presentation Antigens Aqueous Humor Arthritis Autoimmunity Behcet Syndrome Behcet&apos s eye disease Binding Biological Biological Models Blindness CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cells Cellular Immunity Clonal Expansion Clonality Clone Cells Code Data Data Analyses Disease East Asian Effector Cell Endoplasmic Reticulum European Event Eye Eye diseases Flow Cytometry Frequencies Genes Genetic Epistasis Genetic Polymorphism Goals HLA Antigens Haplotypes Hispanic Americans Histocompatibility Antigens Class I Immune Immune System Diseases Immune response Immunogenetics Inflammation Inflammatory Inflammatory Bowel Diseases International Knock-out Knowledge Link Liquid substance Literature Mediating Memory Methods Middle Eastern Outcome Pathogenesis Pathway interactions Patients Peptides Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Population Prevalence Proteins Psoriasis Public Health Publishing Research Risk Role Shapes Spondylitis Systemic disease T cell response T-Lymphocyte TCR Activation Testing Uveitis Variant anterior chamber cell type cohort computerized tools design effector T cell experience genome editing gut inflammation high risk immune function meetings rational design receptor receptor function response risk variant side effect single-cell RNA sequencing targeted treatment therapy design transcriptomics

项目摘要

ABSTRACT / PROJECT SUMMARY HLA-B*51 in epistasis with the ERAP1 haplotype Hap10 confers the strongest currently known risk for Behcet’s Disease (BD) and Behcet’s Eye Disease (BED), but the consequences of this relationship for immune-phenotype, clonality, and function, are entirely unknown. The main objective of this application is to identify these consequences. This is in line with our long-term goal to find, comprehend, and correct aberrancies in immune pathways that drive Behcet’s Eye Disease (BED). Based on our preliminary studies we propose as our central hypothesis that ERAP1 Hap10 shapes immune responses in HLA-B*51+ BED through the activation of clonal CD8 T and NKT effector cell populations that drive the disease. We follow the rationale that elucidation of the biological consequences of HLA-B51/ERAP1 Hap10 will promote a mechanistic understanding of BED in affected carriers, and therefore enable targeted therapy design. We will test our central hypothesis in two specific aims: 1) Through the determination of immune phenotypes linked to HLA-B*51+/ERAP1 Hap10 BED, combining access to unique patient cohorts of our own and those of our international collaborators with large-scale flow cytometric analyses using computational tools we have developed. 2) Through the identification of clonal effector responses and function in BED patients using single cell-transcriptomics and methods of T cell cloning we have established. Meeting the objective of this proposal will generate knowledge providing scientific rationale for the design of targeted therapies for BED, which is one of the most devastating forms of non-infectious uveitis with significant prevalence in large parts of the world. We expect additional positive impact by cross-fertilizing research of other HLA-I/ERAP-related diseases including HLA-B27-associated uveitis and spondylitis, Birdshot’s choroidopathy, psoriasis-associated conditions, and inflammatory bowel disease (IBD).

摘要/项目总结 HLA-B*51与ERAP 1单倍型Hap 10的上位性赋予了目前已知的最强的白塞氏病（BD）和白塞氏眼病（BED）的风险，但这种关系对免疫表型、克隆性和功能的影响是完全未知的。本申请的主要目的是确定这些后果。这符合我们的长期目标，即发现，理解和纠正驱动白塞氏眼病（BED）的免疫途径中的异常。基于我们的初步研究，我们提出了我们的中心假设，即ERAP 1 Hap 10通过激活驱动疾病的克隆CD 8 T和NKT效应细胞群体来塑造HLA-B*51+ BED中的免疫应答。我们遵循的基本原理是，阐明HLA-B51/ERAP 1 Hap 10的生物学后果将促进对受影响携带者中BED的机制理解，从而实现靶向治疗设计。我们将在两个具体目标中测试我们的中心假设：1）通过确定与HLA-B*51+/ERAP 1 Hap 10 BED相关的免疫表型，结合我们自己和我们的国际合作者的独特患者队列，使用我们开发的计算工具进行大规模流式细胞术分析。2)通过使用单细胞转录组学和T细胞克隆方法鉴定BED患者的克隆效应反应和功能，我们建立了。满足本提案的目标将产生知识，为BED的靶向治疗设计提供科学依据，BED是世界大部分地区最具破坏性的非感染性葡萄膜炎之一。我们期望通过对其他HLA-I/ERAP相关疾病的交叉研究，包括HLA-B27相关的葡萄膜炎和脊柱炎，Birdshot脉络膜病变，银屑病相关疾病和炎症性肠病（IBD），产生额外的积极影响。