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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 基因拷贝数（GCN）变异是一种新描述的现象，它可能在人群中造成显着的表型变异性。在编码防御素，阳离子抗菌胡椒的基因中，呈现了实质性的GCN变异，这些基因在先天免疫学中对传染病起着重要作用。编码� -defensin 2的基因是皮肤和粘膜表面上先天免疫反应的关键部分，从每个二倍体基因组的2-12份不等。最近的证据将BD2 GCN的变异与对特发性疾病的易感性联系在一起：低GCN增加了Crohn结肠病的风险，而高GCN则与牛皮癣的风险增加有关。我们最近使用恒河猴模型来证明，与人类一样，BD2表达是由幽门螺杆菌诱导的，幽门螺杆菌是一种常见的胃病原体，是消化性溃疡的病因，并增加了胃癌的风险。此外，我们的初步数据表明，像人类一样，恒河猕猴在BD2 GCN中具有明显的变化。我们假设BD2GCN的变化反映在BD2的表达水平上，并且这些差异将影响幽门螺杆菌感染的结果。在AIM 1中，我们将表征猕猴BD2基因中的GCN和等位基因多样性，并检查原代细胞培养中GCN与BD2表达之间的关系。在AIM 2中，我们将确定三组具有低，中间或高BD2 GNC的猕猴，并将其胃Biota和对实验挑战的反应与幽门螺杆菌进行比较。由于只有大约5至10％的幽门螺杆菌感染的人将具有临床后遗症，而其余的只有无症状的胃炎，因此了解与疾病相关的宿主因素有很大的兴趣。因此，了解BD2基因和幽门螺杆菌感染的遗传变异之间的功能关系不仅会扩大我们对先天免疫反应和感染之间关系的了解，而且还可以提供转化联系，以更好地了解谁可以从幽门螺杆菌治疗中受益，以防止肽Ulcer和胃癌。