Pathogenesis of virus-induced acute otitis media

描述（由研究者提供）：中耳炎（OM）是儿科实践中最常见的疾病，被认为是一种多因素疾病，具有复杂且相互关联的遗传、环境和感染病因。我们研究小组的长期目标是阐明感染性病原体的贡献，以及它们与急性中耳炎（AOM）发病机制和恢复中其他OM危险因素的复杂相互作用，并确定更有效预防和/或治疗的可能策略。我们最近发现，促炎细胞因子基因多态性（TNF-1 -308和IL- 6-174）和OM易感性增加之间存在重要关联，以及环境因素（如母乳喂养（BF）和香烟烟雾暴露（CSE））对多态个体OM易感性的可能修饰作用。在下一个资助期内，我们建议进一步研究病毒诱导的AOM的发病机制，特别是遗传风险因素（如TNF 1 -308和IL- 6-174多态性）使宿主OM易感的机制，以及环境因素是否可以改变遗传易感儿童的OM风险。目标1：对300名有和无TNF 1 -308多态性的婴儿进行前瞻性病例对照研究，随访至首次AOM发作1岁。将对受试者进行基因多态性筛选;将在出生后第一个月内入组相同数量的多态性和正常婴儿（性别和人种匹配）。前6个月鼻咽部细菌定植的动态变化。将研究生命的时间;将监测症状性URI发作的AOM并发症。将前瞻性收集BF、CSE和DC出勤信息，并不断更新。将在多态性和正常儿童组之间比较出生后第一年AOM的发生率（第一年至少发生一次的病例百分比）;将评估环境风险因素对细菌定植、病毒性URI和AOM发生率的影响。样本量也足以在IL- 6-174多态性和正常儿童之间进行平行比较。目的2：进一步探讨其他几种细胞因子/趋化因子基因多态性与OM易感性的关系。将使用最先进的微阵列技术检测来自拟定研究1（来自OM易感和非OM易感儿童，n=800）的存档和新DNA样本的11种细胞因子/趋化因子基因多态性。基因多态性将与OM易感性相关;数据挖掘将用于分析复杂的数据。从我们的研究中产生的信息将对公共卫生非常重要，因为它将为设计预防OM的创新方法奠定基础，特别是在出生时具有遗传易感性的儿童和暴露于OM环境风险的儿童中。公共卫生相关性中耳炎是婴儿和儿童中的一种高度流行的疾病。这项研究与公共卫生有关，因为所产生的信息将成为设计预防中耳炎的创新方法的基础，特别是在出生时具有遗传易感性的儿童和暴露于OM环境风险的儿童中。

DESCRIPTION (provided by investigator): Otitis media (OM) is the most common disease seen in pediatric practice and is recognized as a multifactorial disease with complex and interrelated genetic, environmental and infectious etiologies. The long- term objectives of our research group are to elucidate the contribution of infectious pathogens, and their complex interactions with other OM risk factors in the pathogenesis of and recovery from acute otitis media (AOM), and to identify possible strategies for more effective prevention and/or treatment. We have recently found an important association between proinflammatory cytokine gene polymorphisms (TNF1-308 and IL- 6-174) and increased OM susceptibility, and possible modifying effects of environmental factors such as breastfeeding (BF) and cigarette smoke exposure (CSE) on OM susceptibility in polymorphic individuals. During the next funding period, we propose to study further the pathogenesis of virus-induced AOM, specifically on the mechanisms by which genetic risk factors (as represented by TNF1-308 and IL- 6-174 polymorphisms) render the host OM susceptible and whether environmental factors could modify OM risks in children with genetic predisposition. Aim 1: Perform a prospective, case-control study of 300 infants with and without TNF1-308 polymorphism followed to the first AOM episode up to 1 year of age. Subjects will be screened for the gene polymorphism; equal number of polymorphic and normal infants (matched for gender and race) will be enrolled into the study within the first month of life. The dynamics of nasopharyngeal bacterial colonization in the first 6 mos. of life will be studied; symptomatic URI episodes will be monitored for AOM complication. Information on BF, CSE, and DC attendance will be collected prospectively and updated continuously. Incidence of AOM in the first year of life (per cent of cases with at least one episode in the first year) will be compared between polymorphic and normal children groups; modifying effects of environmental risk factors on bacterial colonization, incidence of viral URI and AOM will be assessed. Sample size will also be adequate for parallel comparison between IL- 6-174 polymorphic and normal children. Aim 2: Investigate further the association between several other cytokine/ chemokine gene polymorphisms and OM susceptibility. Archived and new DNA samples from the proposed Study 1 (from OM-susceptible and non-OM susceptible children, n=800) will be tested for 11 cytokine/ chemokine gene polymorphisms using the state-of-the-art microarray technique. Gene polymorphisms will be associated with OM susceptibility; data mining will be used to analyze complex data. Information generated from our studies will be important to public health as it will lay the ground work for the design of innovative approaches to prevent OM, especially in children born with genetic predisposition and those exposed to OM environmental risks. PUBLIC HEALTH RELEVANCE Otitis media is a highly prevalent disease in infants and children. This study is relevant to public health because information to be generated will be the basis for the design of innovative approaches to prevent otitis media, especially in children born with genetic predisposition and those exposed to OM environmental risks.