Risk factors for gastric disease in pediatric H. pylori

儿童幽门螺杆菌胃病的危险因素

• 批准号: 6778813
• 负责人: BENJAMIN David GOLD
• 金额: $ 37.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778813
• 关键词: Helicobacter; bacterial cytopathogenic effect; bacterial genetics; clinical research; disease /disorder etiology; disease /disorder proneness /risk; environmental exposure; enzyme linked immunosorbent assay; gastrointestinal disorder; gene expression; genetic strain; genome; helper T lymphocyte; histology; host organism interaction; immune response; microarray technology; microorganism immunology; mucosal immunity; pediatrics; phenotype; polymerase chain reaction; sign /symptom; statistics /biometry; virulence

DESCRIPTION (provided by applicant): Helicobacter pylori (Hp) is a major cause of chronic-active gastritis, primary duodenal ulcers and strongly linked to gastric cancer. Most Hp infections worldwide are acquired in childhood. Why some individuals develop symptomatic disease is unclear and, until recently, no studies critically evaluated the role of pediatric Hp strains and/or host factors in disease outcomes. Over the past 5 years of NIH funding, 486 children from Atlanta, Cleveland, and Miami were enrolled; 184 (38%) were Hp-infected. Race (African American) and younger age, in conjunction with Hp strains expressing cagA and vacAs1 B, were shown to be risk factors for both esophageal and gastric disease; suggesting a different disease paradigm from Hp-infected adults. Using the Updated Sydney system, we demonstrated a histopathologic spectrum in children, which included novel observations of atrophic gastritis with intestinal metaplasia. Overall hypothesis for competitive renewal: disease manifestations in Hp-infected children are influenced by specific host factors (i.e., race, immune phenotype), environmental exposures, and specific virulence factors of infecting Hp strains. Specific aims: 1) Using well defined cases and controls, further characterize specific host factors and environmental exposures contributing to symptomatic childhood infection emphasizing targeted enrollment in specific age, gender and demographic strata to facilitate detection of significant differences not attained previously and follow up of 2 established specific cohorts to ascertain immune response natural history. 2) Utilize gene-array technology for whole Hp genome assessment and bacterial gene expression of specific virulence determinants associated with pediatric Hp strains. 3) Further, characterize the host immunologic and mucosal response in Hp infected children. Hp-infected symptomatic endoscopy cases at our established three clinical centers of high, moderate and low tip prevalence will be compared with age-matched Hp-infected asymptomatic and uninfected symptomatic controls. Two geographically and demographically distinct centers have been added to provide additional geographic and subject representativeness to the patient cohort. The Updated Sydney system will be employed to assess gastric histopathology severity and phenotype in newly enrolled cases in specific age, gender and demographic strata and follow-up of the two "novel" cohorts established in the past 5 years; a) atrophic gastritis; b) esophageal and gastric disease group enabling a comprehensive, multivariate evaluation of the natural history of Hp-infected children in two distinct disease paradigms. Using molecular methods (multiplex [MP]-PCR, RT-PCR) and a micro ELISPOT assay on peripheral blood mononuclear cells (PBMCS), Th1, Th2, Th3 or balanced Th1/Th2 response will be determined to further characterize the Hp-infected child's immune response phenotype. We propose to further our previous work with critically lacking studies from a multivariate approach leading to a better understanding of the gastroduodenal disease sequelae and overall pathobiology of Hp infection in humans.

描述(申请人提供)：幽门螺杆菌(HP)是慢性活动性胃炎、原发性十二指肠溃疡的主要原因，与胃癌密切相关。全球大多数Hp感染都是在儿童时期感染的。为什么有些人会患上症状性疾病尚不清楚，而且直到最近，还没有研究对儿童Hp菌株和/或宿主因素在疾病结局中的作用进行严格评估。在NIH过去5年的资助中，来自亚特兰大、克利夫兰和迈阿密的486名儿童参加了研究；184名儿童(38%)感染了Hp。种族(非裔美国人)和更年轻的年龄，以及表达cagA和VacAs1B的Hp菌株，被证明是食道和胃疾病的危险因素；这表明了与Hp感染的成年人不同的疾病范式。使用最新的悉尼系统，我们展示了儿童的组织病理学谱，其中包括萎缩性胃炎伴肠上皮化生的新观察。竞争更新的总体假设：感染Hp的儿童的疾病表现受到特定宿主因素(即种族、免疫表型)、环境暴露和感染Hp菌株的特定毒力因素的影响。具体目标：1)利用明确的病例和对照，进一步确定导致儿童症状感染的特定宿主因素和环境暴露的特征，强调在特定的年龄、性别和人口层面进行有针对性的登记，以便于发现以前没有达到的显著差异，并对2个已建立的特定队列进行跟踪，以确定免疫反应的自然病史。2)利用基因芯片技术对幽门螺杆菌全基因组进行评估，并对与儿童幽门螺杆菌菌株相关的特异性毒力决定因素进行基因表达。3)进一步了解幽门螺杆菌感染儿童的宿主免疫反应和粘膜反应。在我们建立的高、中、低TIP患病率的三个临床中心，幽门螺杆菌感染的症状性内窥镜病例将与年龄匹配的幽门螺杆菌感染的无症状和未感染的症状对照进行比较。增加了两个地理和人口统计学上截然不同的中心，为患者队列提供额外的地理和受试者代表性。最新的悉尼系统将被用来评估特定年龄、性别和人口层面的新登记病例的组织病理学严重性和表型，并对过去5年建立的两个“新”队列进行跟踪：a)萎缩性胃炎；b)食道和胃病组，使之能够在两种不同的疾病范例中对HP感染儿童的自然病史进行全面的、多变量的评估。使用分子方法(多重[MP]-PCR、RT-PCR)和微量ELISPOT分析外周血单个核细胞(PBMCS)，将检测Th1、Th2、Th3或Th1/Th2平衡反应，以进一步表征Hp感染儿童的免疫反应表型。我们建议进一步我们之前的工作，从多变量方法缺乏严重缺乏的研究，导致更好地了解胃十二指肠疾病后遗症和人类Hp感染的整体病理生物学。