ER-localized aminopeptidases in ankylosing spondylitis

强直性脊柱炎中内质网定位的氨肽酶

基本信息

批准号：
7983691
负责人：
Andrea na Amalfitano
金额：
$ 29.61万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983691
关键词：
Affect Age of Onset Alleles Aminopeptidase Animal Model Ankylosing spondylitis Antigen Presentation Autoimmune Diseases Binding Biochemical Biological Biological Assay Cell Culture Techniques Chronic Clinical Collaborations Cultured Cells Cytokine Receptors Cytotoxic T-Lymphocytes Diagnosis Disease Environmental Risk Factor Epitopes Frequencies Genes Genetic Genetic Polymorphism Genomics Goals HLA-B27 Antigen Histocompatibility Antigens Class I Human Immune response Individual Knockout Mice Knowledge Lead Link MHC Class I Genes Measures Methods Molecular Molecular Target Mus Nature Onset of illness Pain Pathogenesis Pathway interactions Peptides Predisposition Prevention Research Risk Role Substrate Specificity Symptoms System Techniques Testing Transgenic Mice Transgenic Organisms Variant antigen processing clinically significant experience genetic association high risk in vivo mouse model novel novel strategies outcome forecast preference prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Ankylosing spondylitis (AS) is a painful, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both environmental and genetic factors are involved in the disease, the cause and pathogenesis of AS remain unclear. A strong link with the MHC class I allele HLA-B27 has implicated antigen processing as an underlying factor, and this hypothesis was strengthened by the recent demonstration that polymorphisms in ERAP1 (an aminopeptidase that we and others have shown is associated with antigen processing) affect the risk of developing AS. We hypothesize that ERAP1 polymorphisms either directly or indirectly affect substrate selection and trimming, so that different ERAP1 alleles alter the levels of arthritogenic or protective peptides presented on HLA-B27. We will test this hypothesis using biochemical assays for substrate specificity, cultured cells to measure effects on antigen processing, and transgenic mice to test effects on disease in vivo. We will also test the effects of ERAP1 polymorphisms on other pathways that have been proposed to affect AS pathogenesis, including the assembly and stability of HLA- B27 and shedding of cytokine receptors. The Aims of this project are to determine the functional effects of ERAP1 polymorphisms and to understand the molecular pathogenesis of AS. The long-term goals of this project are to predict the risk of AS in individuals, and to develop methods to prevent and treat AS. We will also apply the understanding of AS pathogenesis to other autoimmune diseases that are linked to MHC class I alleles. PUBLIC HEALTH RELEVANCE: Ankylosing spondylitis is a painful, chronic, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both genetic and environmental factors are involved, the underlying causes and mechanisms of the disease are not known. In this project I will take advantage of a recently-described association with the gene ERAP1 to identify mechanisms that cause ankylosing spondylitis, with the ultimate goal of developing new techniques to predict the risk of ankylosing spondylitis, and to prevent and treat the disease.

描述（由申请人提供）：强直性脊柱炎（AS）是一种痛苦，无法治愈的自身免疫性疾病，影响了全球数百万的人。尽管很明显，环境因素和遗传因素都涉及该疾病，但AS的原因和发病机理仍不清楚。与MHC I类等位基因HLA-B27的紧密联系将抗原加工作为潜在因素，并且最近证明了ERAP1中的多态性（我们和其他我们和其他人与抗原处理相关的氨基肽酶）影响了发展的风险。我们假设ERAP1多态性直接或间接影响底物的选择和修剪，因此不同的ERAP1等位基因会改变HLA-B27上呈现的关节肽或保护性肽的水平。我们将使用生化测定法对底物特异性，培养细胞进行测量对抗原加工的影响以及转基因小鼠的影响以测试体内对疾病的作用的影响。我们还将测试ERAP1多态性对已提议作为发病机理的其他途径的影响，包括HLA-B27的组装和稳定性以及细胞因子受体的脱落。该项目的目的是确定ERAP1多态性的功能效应，并了解AS的分子发病机理。该项目的长期目标是预测个人的风险，并开发预防和治疗AS的方法。我们还将将对作为发病机理的理解应用于与MHC I类等位基因相关的其他自身免疫性疾病。公共卫生相关性：强直性脊柱炎是一种痛苦，慢性，无法治愈的自身免疫性疾病，影响了全球数百万的人。尽管显然涉及遗传因素和环境因素，但疾病的潜在原因和机制尚不清楚。在这个项目中，我将利用最近描述的与基因ERAP1的关联，以识别引起强直性脊柱炎的机制，其最终目的是开发新技术以预测强直性脊柱炎的风险，并预防和治疗疾病。