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）是一种痛苦且无法治愈的自身免疫性疾病，影响着全世界数百万人。尽管明确环境和遗传因素均与该疾病有关，但 AS 的病因和发病机制仍不清楚。与 MHC I 类等位基因 HLA-B27 的密切联系表明抗原加工是一个潜在因素，并且最近的证明证实了这一假设，即 ERAP1（我们和其他人已经证明的一种氨肽酶与抗原加工相关）的多态性影响发生 AS 的风险。我们假设 ERAP1 多态性直接或间接影响底物选择和修剪，因此不同的 ERAP1 等位基因改变 HLA-B27 上呈递的致关节炎或保护性肽的水平。我们将使用生化测定来测试底物特异性，使用培养细胞来测量对抗原加工的影响，并使用转基因小鼠来测试对体内疾病的影响，来测试这一假设。我们还将测试 ERAP1 多态性对其他影响 AS 发病机制的途径的影响，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 的分子发病机制。该项目的长期目标是预测个体患 AS 的风险，并开发预防和治疗 AS 的方法。我们还将把对 AS 发病机制的理解应用于与 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的、慢性的、无法治愈的自身免疫性疾病，影响着全世界数百万人。尽管很明显遗传和环境因素都参与其中，但该疾病的根本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 的关联来确定导致强直性脊柱炎的机制，最终目标是开发新技术来预测强直性脊柱炎的风险，并预防和治疗该疾病。