Pathogenesis of pneumococcal otitis media

肺炎球菌性中耳炎的发病机制

基本信息

批准号：
8884128
负责人：
Jian-Dong Li
金额：
$ 31.98万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884128
关键词：
Accounting Acute Animal Model Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Chemicals Child Childhood Chronic Clinical Conductive hearing loss DUSP1 gene Data Defensins Deubiquitination Enhancers Foundations Goals Gram-Positive Bacteria Health Hearing Homeostasis Host Defense Hydrogels Immune Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Lead MAPK3 gene MEKs Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mus Oral Otitis Media Otitis Media with Effusion Pathogenesis Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Play Pneumococcal vaccine Protein Dephosphorylation Regulation Role Solid Streptococcus pneumoniae Therapeutic Therapeutic Agents Tympanic membrane Ubiquitination Vaccines Visit antimicrobial base cost defense response hearing impairment immunopathology improved in vivo innovation middle ear mouse model nervous system disorder novel novel therapeutics response socioeconomics vinpocetine

项目摘要

DESCRIPTION (provided by applicant): Otitis media (OM) is the most common childhood bacterial infection and the leading cause of hearing loss. It remains a major health problem and a substantial socioeconomic burden. S. pneumoniae (Sp) is a major gram-positive bacteria causing OM. Current vaccine has a limited impact on OM and inappropriate antibiotic use increased antibiotic-resistance. To date there have been no effective non-antibiotic therapeutic agents available for OM due to poor understanding of Sp pathogenesis. Appropriate innate immune response is critical for host defense in children. However, if uncontrolled, excessive inflammatory response often results in immunopathology and impaired function of middle ear. Thus, innate inflammatory response must be tightly controlled. However, the key regulators and the underlying mechanisms remain largely unknown. Our long-term goal is to understand the molecular mechanisms underlying the tight control of innate inflammatory & host defense response in Sp-induced OM pathogenesis and develop novel non-antibiotic therapeutics. We previously showed that MAP kinase ERK1 positively mediates pathological responses whereas deubiquitinase CYLD and phosphatase MKP-1 act as key negative regulators of pathological responses. Thus, we hypothesized that CYLD and MKP-1 may tightly regulate Sp-induced inflammation and host defense via inhibiting ERK1 by deubiquitinating and dephosphorylating it, and up-regulating CYLD and MKP-1 may represent an ideal and novel therapeutic strategy to inhibit excessive inflammation and maintain an appropriate host defense. Indeed, our preliminary studies demonstrate that CYLD and MKP-1 act as negative regulators for Sp-induced inflammation, but positive regulators for antimicrobial ß-defensin, likely via inhibiting ERK1; Excitingly, systemic and CPE-mediated ototopical administration of Vinpocetine, an existing drug for neurological diseases, suppressed inflammation, improved hearing loss and enhanced ß-defensin induction and bacterial clearance likely via up-regulating CYLD and MKP-1. Vinpocetine also inhibited inflammation and improved hearing in a well-established model of chronic OM. These exciting preliminary data have thus laid a solid foundation for us to further investigate the mechanisms underlying tight regulation of Sp-induced innate inflammatory & host defense responses and evaluate the therapeutic potential of Vinpocetine in OM. Our specific aims are: Aim 1. Determine how Sp-induced innate inflammatory & host defense responses are tightly controlled by inhibiting ERK1. Aim 2. Determine how Vinpocetine inhibits Sp-induced inflammation and enhances host defense. Aim 3. Determine the therapeutic potential of oral and ototopical administration of Vinpocetine in suppressing Sp-induced inflammation and enhancing host defense in acute and chronic OM animal models. Overall, the proposed studies will advance our understanding of molecular pathogenesis of Sp-induced OM and may lead to novel therapeutic strategy to suppress overactive inflammation, improve middle ear hearing function and enhance host defense for Sp-induced OM (Impact & Significance).

描述（由申请人提供）：中耳炎（OM）是最常见的儿童细菌感染，也是听力损失的主要原因，它仍然是一个主要的健康问题，肺炎链球菌（Sp）是一个主要的慢性负担。导致 OM 的阳性细菌。目前的疫苗对 OM 的影响有限，并且由于对 Sp 发病机制的了解不足，迄今为止还没有有效的非抗生素治疗药物可用于 OM。先天性免疫反应对于儿童的宿主防御至关重要，但是，如果不加以控制，过度的炎症反应通常会导致免疫病理学和中耳功能受损，因此，必须严格控制先天性炎症反应，但关键的调节因素和潜在机制仍然存在。我们的长期目标是了解 Sp 诱导的 OM 发病机制中严格控制先天炎症和宿主防御反应的分子机制，并开发新的非抗生素疗法。因此，我们发现 CYLD 和 MKP-1 可能通过去泛素化和去磷酸化来抑制 ERK1，从而严格调节 Sp 诱导的炎症和宿主防御。 -调节 CYLD 和 MKP-1 可能代表一种理想的治疗性新策略，可以抑制过度炎症并维持适当的宿主防御。事实上，我们的初步研究表明， CYLD 和 MKP-1 作为 Sp 诱导的炎症的负调节剂，但作为抗菌 ß-防御素的正调节剂，可能通过抑制 ERK1 来发挥作用；令人兴奋的是，长春西汀（一种治疗神经系统疾病的现有药物）的全身和 CPE 介导的耳局部给药可抑制炎症。，改善听力损失并增强 ß-防御素诱导和细菌清除可能是通过上调 CYLD 和 MKP-1 来抑制炎症和炎症。这些令人兴奋的初步数据为我们进一步研究 Sp 诱导的先天炎症和宿主防御反应的严格调节机制并评估长春西汀的治疗潜力奠定了坚实的基础。 OM. 我们的具体目标是：目标 1. 确定如何通过抑制 ERK1 严格控制 Sp 诱导的先天炎症和宿主防御反应目标 2. 确定长春西汀如何抑制 Sp 诱导的炎症并增强。目标 3. 确定长春西汀口服和耳局部给药在抑制 Sp 诱导的炎症和增强急性和慢性 OM 动物模型中宿主防御方面的治疗潜力。总体而言，拟议的研究将增进我们对 Sp 分子发病机制的理解。诱导的 OM，并可能产生新的治疗策略，以抑制过度活跃的炎症、改善中耳听力功能并增强宿主对 Sp 诱导的 OM 的防御（影响和意义）。