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: 7819960
• 负责人: Charles L Bevins
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-14 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7819960
• 关键词: Acute; Address; Affect; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Applications Grants; Biopsy; Biota; Cells; Cessation of life; Clinical; Communicable Diseases; Complex; Copy Number Polymorphism; Crohn' s disease; DNA; Data; Defensins; Detection; Diploidy; Disease; Disease susceptibility; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epithelial; Event; Future; Gastritis; Gene Dosage; Gene Family; Genes; Genetic; Genetic Variation; Genome; Genus Cola; Helicobacter Infections; Helicobacter pylori; Histopathology; Host Defense; Human; Immune; Immune response; Immunoassay; Immunohistochemistry; In Vitro; Infection; Inflammatory Response; Integration Host Factors; Knowledge; Link; Macaca; Macaca mulatta; Microbe; Modeling; Mucosal Immunity; Names; Natural Immunity; Nomenclature; Outcome; Peptic Ulcer; Peptides; Play; Population; Predisposition; Primary Cell Cultures; Protein Isoforms; Psoriasis; Recombinants; Reporting; Risk; Role; Skin; Stomach; Surface; Testing; Variant; antimicrobial; beta-Defensins; beta-defensin-2; cytokine; genetic variant; innovation; intercellular communication; interest; malignant stomach neoplasm; paralogous gene; pathogen; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): 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 BD2 GCN 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 5 to 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. PUBLIC HEALTH RELEVANCE: ?-defensin2 (BD2) is an important innate immune effectors at epithelial surfaces that shows variability in gene copy number (GCN) and is induced by infection with Helicobacter pylori, an important gastric pathogen. We hypothesize that differences in BD2 GCN affect the host inflammatory response, and thus the propensity to develop disease after infection with H. pylori.

描述（由申请人提供）：基因拷贝数（GCN）变异是一种新描述的现象，可能导致群体内显著的表型变异。大量的GCN变异存在于编码防御素的基因中，防御素是阳离子抗微生物肽，在对感染性疾病的先天免疫中起重要作用。编码β-防御素2的基因是皮肤和粘膜表面先天免疫应答的关键部分，每个二倍体基因组有2-12个拷贝。最近的证据表明，BD 2 GCN的变异与特发性疾病的易感性有关：低GCN增加了结肠克罗恩病的风险，而高GCN与银屑病的风险增加有关。我们最近使用恒河猴模型来证明，像在人类中一样，BD 2的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，是消化性溃疡的病原体，并增加胃癌的风险。此外，我们的初步数据表明，恒河猴，像人类一样，在BD 2 GCN有显着的变化。我们假设BD 2 GCN的变异反映在BD 2的表达水平上，并且这些差异将影响H.幽门。在目标1中，我们将描述猕猴BD 2基因中的GCN和等位基因多样性，并研究GCN和原代细胞培养中BD 2表达之间的关系。在目标2中，我们将确定三组具有低、中或高BD 2 GNC的猕猴，并比较它们的胃生物群和对H.幽门。因为只有大约5%到10%的人感染H.幽门螺杆菌感染者会有临床后遗症，而其余的人只会有无症状的胃炎，因此人们对了解与疾病相关的宿主因素有相当大的兴趣。了解BD 2基因的遗传变异与H.因此，幽门螺杆菌感染不仅将扩大我们对先天免疫反应与感染之间关系的了解，而且还可能提供翻译联系，以更好地了解谁可能从幽门螺杆菌治疗中受益。幽门螺杆菌，以防止消化性溃疡和胃癌。 公共卫生相关性：防御素2（defensin 2，BD 2）是上皮细胞表面的一种重要的先天性免疫效应物，其基因拷贝数（gene copy number，GCN）具有变异性，并且由幽门螺杆菌（Helicobacter pylori）（一种重要的胃病原体）感染诱导。我们假设BD 2 GCN的差异影响宿主的炎症反应，从而影响感染H.幽门。