DEFENSIN GENE COPY NUMBER AND MUCOSAL INNATE IMMUNITY

防御素基因拷贝数和粘膜先天免疫

• 批准号: 8357354
• 负责人: JAY V. SOLNICK
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357354
• 关键词: Affect; Antimicrobial Cationic Peptides; Biota; California; Clinical; Colon; Communicable Diseases; Copy Number Polymorphism; Crohn' s disease; Data; Defensins; Diploidy; Disease; Funding; Gastritis; Gene Dosage; Genes; Genetic Variation; Genome; Grant; Helicobacter Infections; Helicobacter pylori; Human; Immune response; Infection; Integration Host Factors; Knowledge; Link; Macaca; Macaca mulatta; Modeling; National Center for Research Resources; Natural Immunity; Outcome; Peptic Ulcer; Play; Population; Predisposition; Primary Cell Cultures; Primates; Principal Investigator; Psoriasis; Research; Research Infrastructure; Resources; Risk; Role; Skin; Source; Stomach; Surface; United States National Institutes of Health; Variant; cost; interest; malignant stomach neoplasm; pathogen; prevent; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gene copy number (GCN) variation is a newly described phenomenon, which likely contributes significant phenotypic variability within populations. Substantial GCN variation is present in genes that encode defensins, cationic antimicrobial peptides that play an important role in innate immunity to infectious diseases. The gene encoding ¿-defensin 2, which is a key part the innate immune response in skin and mucosal surfaces, varies from 2-12 copies per diploid genome. Recent evidence has linked variation in the BD2 GCN with susceptibility to idiopathic diseases: low GCN increases the risk for Crohn's disease of the colon, while high GCN is associated with increased risk of psoriasis. We recently used the rhesus macaque model to demonstrate that, like in humans, BD2 expression is induced by Helicobacter pylori, a common gastric pathogen that is the causative agent of peptic ulcer and increases the risk for gastric cancer. Furthermore, our preliminary data suggest that rhesus macaques, like humans, have marked variation in BD2 GCN. We hypothesize that variation in BD2GCN is reflected in expression levels of BD2, and that these differences will affect the outcome of infection with H. pylori. In Aim 1 we will characterize GCN and allelic diversity in the BD2 gene of macaques, and examine the relationship between GCN and expression of BD2 in primary cell culture. In Aim 2 we will identify three groups of macaques with low, intermediate, or high BD2 GNC, and compare their gastric biota and response to experimental challenge with H. pylori. Since only about 5to 10% of humans infected with H. pylori will have clinical sequelae, while the remainder will have only asymptomatic gastritis, there is considerable interest in understanding host factors that are associated with disease. Understanding the functional relationship between genetic variations in the BD2 gene and H. pylori infection will therefore not only expand our knowledge of the relationship between the innate immune response and infection, but may also provide a translational link to better understand who may benefit from treatment of H. pylori in order to prevent peptic ulcer and gastric cancer.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 基因拷贝数（GCN）变异是一种新描述的现象，它可能导致群体内显着的表型变异。编码防御素的基因中存在大量的GCN变异，而防御素是在传染病的先天免疫中发挥重要作用的基因。编码 ¿ -防御素 2 是皮肤和粘膜表面先天免疫反应的关键部分，每个二倍体基因组有 2-12 个拷贝，最近的证据表明 BD2 GCN 的变异与特发性疾病的易感性有关：低 GCN 会增加患特发性疾病的风险。结肠克罗恩病，而高 GCN 与牛皮癣风险增加有关，我们最近使用恒河猴模型证明，与人类一样， BD2 表达是由幽门螺杆菌诱导的，幽门螺杆菌是消化性溃疡的致病菌，会增加患胃癌的风险。此外，我们的初步数据表明，恒河猴与人类一样，BD2 GCN 也存在显着变异。 BD2GCN 中的差异反映在 BD2 的表达水平上，这些差异将影响幽门螺杆菌感染的结果。在目标 1 中，我们将描述 GCN 和 H. pylori 的特征。在目标 2 中，我们将鉴定三组具有低、中或高 BD2 GNC 的猕猴，并比较它们的胃生物群和胃生物群。由于只有大约 5% 至 10% 的感染幽门螺杆菌的人会出现临床后遗症，而其余的人只会出现无症状。胃炎，人们对了解与疾病相关的宿主因素非常感兴趣，了解 BD2 基因的遗传变异与幽门螺杆菌感染之间的功能关系不仅将扩大我们对先天免疫反应与感染之间关系的认识，但也可能提供翻译链接，以更好地了解谁可以从幽门螺杆菌治疗中受益，以预防消化性溃疡和胃癌。