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：
10328964
负责人：
Johannes Nowatzky
金额：
$ 41.1万
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/10328964
关键词：
Affect Age Ankylosing spondylitis Antigen Presentation Antigens Aqueous Humor Arthritis Autoimmunity Behcet Syndrome Biological Biological Models Blindness CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cells Cellular Immunity 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 I-antigen Immune Immune System Diseases Immune response Immunogenetics Inflammation Inflammatory Inflammatory Bowel Diseases International Knock-out Knowledge Link Liquid substance Literature Mediating Memory Methods 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 base 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 /项目摘要 Hla-b*51在Epitipis中具有ERAP1单倍型HAP10在Behcet疾病（BD）和Behcet的眼病（BED）中引起了强烈的风险，但是这种关系对免疫 - 表型，克隆性和功能的后果是完全未知的。该应用程序的主要目的是确定这些后果。这符合我们的长期目标，即在驱动Behcet眼科（BED）的免疫途径中找到，理解和纠正异常。基于我们的初步研究，我们建议通过激活Clonal CD8 T和NKT效应细胞群体来塑造HLA-B*51+床中的免疫复杂的中心假设，这些疾病驱动了疾病。我们遵循这样的理由，即HLA-B51/ERAP1 HAP10阐明生物学后果将促进对受影响携带者的床的机械理解，从而实现目标治疗设计。我们将在两个具体目标中测试中心假设：1）通过确定与HLA-B*51+/ERAP1 HAP10床相关的免疫表型，结合了我们使用计算机工具的大规模流动细胞量学分析，将我们自己的国际合作者的独特患者访问结合在一起。 2）通过使用单细胞转录组学和T细胞克隆的方法鉴定床患者的克隆效应子反应和功能，我们已经建立了。符合该提案的目标将产生知识，为贝德的靶向疗法设计提供科学原理，这是世界上大部分地区最具毁灭性的非感染葡萄膜炎形式之一。我们期望通过对其他与HLA-I/ERAP相关疾病的研究，包括HLA-B27相关的葡萄膜炎和赞助，Birdshot的脉络膜病变，牛皮癣相关疾病以及炎症性肠病（IBD）。