Effect of the Middle Ear Inflammation on the Inner Ear

中耳炎症对内耳的影响

• 批准号: 8458991
• 负责人: David E Briles
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-16 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458991
• 关键词: 2 year old; Active Immunization; Acute; Address; Adult; Advisory Committees; Affect; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Attenuated; Auditory; Auditory Brainstem Responses; Bacteria; Bacterial Antigens; Bacterial Proteins; Bone Conduction; Child; Childhood; Chronic; Cochlea; Conjugate Vaccines; Data Reporting; Development; Disease; Drug Formulations; Ear; FDA approved; Failure; Foundations; Functional disorder; Future; Genetic; Goals; Haemophilus influenzae; Histology; Host Defense; Human; Immunization; Immunohistochemistry; Infection; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory Response; Investigation; Ion Channel; Labyrinth; Labyrinthitis; Lead; Licensing; Life; Mediating; Membrane; Meningitis; Molecular; Moraxella (Branhamella) catarrhalis; Multi-Drug Resistance; Otitis Media; Pathogenesis; Pathology; Phase; Play; Pneumococcal 7-Valent Conjugate Vaccine; Pneumococcal Infections; Pneumococcal vaccine; Pneumovax; Polysaccharides; Prevention; Prevention strategy; Process; Protein S; Proteins; Public Health; Qualifying; Recurrence; Research; Role; Salmonella; Serotyping; Streptococcus pneumoniae; Testing; Therapeutic Intervention; Toll-like receptors; Vaccine Design; Vaccines; Virulence; Virulence Factors; bacteria characteristic; base; cytokine; design; drug resistant bacteria; early childhood; hearing impairment; innovation; insight; middle ear; migration; mutant; novel strategies; pathogen; prevent; public health relevance; research study; resistant strain; round window; therapeutic target; vaccine development

DESCRIPTION (provided by applicant): Otitis media (OM) is one of the most common of childhood diseases and a major public health problem. The disease can lead to middle ear and inner ear pathology and hearing loss. There are fundamental gaps in our understanding of how bacterial pathogens in OM cause the inflammatory response in the middle ear, the mechanism of middle and inner ear interaction, inner ear pathology, and hearing loss. This prompted us to develop a cogent investigation of the molecular processes underlying migration of infectious agents from the middle to the inner ear and the effects of such migration on the ear pathology. Widespread use of antibiotics has resulted in an increase of antibiotic-resistant Streptococcus pneumoniae and an increased potential for chronic OM development and its complications. Although polysaccharide vaccines have been developed, there are more than 90 distinct serotypes for S. pneumoniae, and antibodies against one serotype generally do not protect against another. The current 7-valent pneumococcal conjugate vaccine PCV7 is 100% efficacious against invasive pneumococcal disease of vaccine serotypes in children < 2-years old, but only 34% against acute OM. A protein-based vaccine may overcome this limitation by including antigens conserved among different pneumococcal serotypes. Our long-term goal is to develop novel approaches for prevention and treatment of OM and its complications. In this application, we propose a new strategy for prevention of OM and its complications that relies on a combination of PspA and other pneumococcal proteins. We will utilize different mutant bacterial strains and immunization of animals against these proteins. Our objective is to understand the role of bacterial virulence factors in bacterial invasion, colonization, and pathogenesis in the middle and inner ears for therapeutic targeting and to develop a vaccine composition that optimally neutralizes the most critical protein virulence factors. Our central hypothesis is that PspA and other bacterial proteins affect the pathology of the middle and inner ears. Bacterial components and inflammatory mediators produced in the middle ear pass through the round window membrane into the inner ear, damage cochlear structures, resulting in hearing loss. Our rationale is that knowing how bacterial components affect the pathology of the middle and inner ears will make it possible to design new approaches for the prevention and treatment of OM. These considerations have led to the formulation of our Specific Aims: 1) To identify the role of pneumococcal PspA protein and its combination with other potential pneumococcal vaccine proteins on the middle and inner ear and strategies for prevention of OM; 2) To identify mechanisms of inner ear damage and auditory dysfunction caused by live S. pneumoniae. The results gained from these studies will provide new insights into the roles of S. pneumoniae virulence factors in the development of OM and inner ear complications. To achieve our goal we have assembled a group of PIs who have collaborated in recent years, and who are uniquely qualified to address this challenge with their combined expertise.

描述（由申请人提供）：中耳炎（OM）是最常见的儿童疾病之一，也是一个主要的公共卫生问题。该疾病可导致中耳和内耳病变以及听力损失。我们对 OM 中的细菌病原体如何引起中耳炎症反应、中耳和内耳相互作用的机制、内耳病理学和听力损失的理解存在根本差距。这促使我们对感染因子从中耳迁移到内耳的分子过程以及这种迁移对耳病理学的影响进行了令人信服的研究。抗生素的广泛使用导致耐抗生素肺炎链球菌的增加，并增加了慢性 OM 及其并发症的可能性。尽管多糖疫苗已经开发出来，但肺炎链球菌有 90 多种不同的血清型，针对一种血清型的抗体通常不能预防另一种血清型。目前的七价肺炎球菌结合疫苗PCV7对2岁以下儿童各疫苗血清型的侵袭性肺炎球菌疾病有100%有效，但对急性OM仅有效34%。基于蛋白质的疫苗可以通过包含不同肺炎球菌血清型之间保守的抗原来克服这一限制。我们的长期目标是开发预防和治疗 OM 及其并发症的新方法。在此应用中，我们提出了一种预防 OM 及其并发症的新策略，该策略依赖于 PspA 和其他肺炎球菌蛋白的组合。我们将利用不同的突变菌株并对动物进行针对这些蛋白质的免疫。我们的目标是了解细菌毒力因子在中耳和内耳细菌入侵、定植和发病机制中的作用，以实现治疗靶向，并开发一种能够最佳地中和最关键的蛋白质毒力因子的疫苗组合物。我们的中心假设是 PspA 和其他细菌蛋白影响中耳和内耳的病理。中耳产生的细菌成分和炎症介质通过圆窗膜进入内耳，损害耳蜗结构，导致听力下降。我们的理由是，了解细菌成分如何影响中耳和内耳的病理学将使设计预防和治疗 OM 的新方法成为可能。这些考虑因素导致我们制定了具体目标： 1) 确定肺炎球菌 PspA 蛋白及其与其他潜在肺炎球菌疫苗蛋白的组合对中耳和内耳的作用以及预防 OM 的策略； 2) 确定活肺炎链球菌引起的内耳损伤和听觉功能障碍的机制。这些研究获得的结果将为了解肺炎链球菌毒力因子在 OM 和内耳并发症的发展中的作用提供新的见解。 为了实现我们的目标，我们召集了一组 PI，他们近年来一直在合作，并且拥有独特的资格，能够凭借其综合专业知识应对这一挑战。