Novel regulation of mucosal innate defense by AMPK in Otitis Media

AMPK 对中耳炎粘膜先天防御的新调节

• 批准号: 10229198
• 负责人: Jian-Dong Li
• 金额: $ 45.98万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10229198
• 关键词: Accounting; Acute; Adenosine; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacterial Infections; Child; Childhood; Chronic; Clinical; Communicable Diseases; Conductive hearing loss; Data; Development; Disease; Down-Regulation; Epithelial Cells; Foundations; Goals; Health; Homeostasis; In Vitro; Inflammation; Lead; Link; Lung infections; Lysine; MUC5AC gene; MUC5B gene; Mediating; Molecular; Mucins; Mucociliary Clearance; Mucosal Immune Responses; Mucous Membrane; Mucous body substance; Obstruction; Otitis Media; Pathogenesis; Phosphorylation; Play; Polyubiquitination; Production; Protein Kinase; Proteins; Public Health; Regulation; Role; Serotyping; Signal Transduction; Solid; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; TLR2 gene; Testing; Therapeutic; Therapeutic Agents; Threonine; Toll-like receptors; Ubiquitination; Up-Regulation; Vaccines; Virulence Factors; Visit; airway epithelium; cost; defense response; human disease; innovation; middle ear; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic bacteria; pathogenic microbe; protein degradation; socioeconomics; vaccine access; virtual

Mucin, a major protein component in mucus, plays a critical role in mucosal innate defense by providing a physical barrier and trapping pathogens for mucociliary clearance. If uncontrolled, excessive mucin production overwhelms mucociliary clearance and causes conductive hearing loss in otitis media (OM) and mucus obstruction in lung infections. Therefore, mucin production must be tightly regulated. However, the molecular mechanisms underlying the tight regulation of mucin remain largely unknown. Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss. It remains a major health problem and a substantial socioeconomic burden. S. pneumoniae, Sp, represents a major gram-positive bacterial pathogen for OM. Currently available Sp vaccines have a limited impact on OM. Moreover, inappropriate antibiotic use increased antibiotic-resistance. There is an urgent need for developing innovative non-antibiotic therapeutic agent for suppressing mucus overproduction. Our long-term goal is to elucidate the molecular mechanisms underlying OM pathogenesis and identify novel therapeutic targets. In contrast to the relatively well-known toll-like receptor (TLR)-dependent mechanisms by which Sp and pneumolysin (PLY – a key virulence factor produced by virtually all clinical Sp isolates) induce host mucosal immune response, the TLR-independent mechanisms including the key regulators remain largely unclear. Adenosine 5’-monophosphate-activated protein kinase α1 (AMPKα1) has emerged as a master regulator of host energy homeostasis. Its role in infectious diseases, in particular in the host mucosal innate defense response, e.g. mucus production, remains largely unclear. Our encouraging preliminary data suggest that Sp and PLY may up-regulate mucin MUC5AC and MUC5B via activation of AMPKα1 in a TLR2/4-independent manner in the middle ear and airway epithelial cells in vitro and in the mouse models of both acute and chronic OM. Interestingly, Sp and PLY may activate AMPKα1 by inducing novel non-traditional (protein degradation- independent) ubiquitination of AMPKα1 likely via downregulating a key deubiquitinase CYLD. Together, these exciting preliminary data have thus provided a solid foundation for us to hypothesize that [1] AMPKα1 acts as a key regulator for Sp-induced up-regulation of MUC5AC and MUC5B via TLR-independent signaling; [2] Activation of AMPKα1 by interplay between polyubiquitination and phosphorylation plays a critical role in Sp- induced up-regulation of MUC5AC and MUC5B (hypothesis). To test our hypothesis, we will pursue two specific aims to determine (Aim 1) the role of AMPKα1 in OM pathogenesis in both AOM and COM; and (Aim 2) how Sp activates AMPKα1. These studies will significantly advance our understanding of the key regulators including AMPK in TLR-independent host mucosal innate defense in bacterial infections and lead to the identification of novel therapeutic targets for controlling mucus overproduction. Our AMPK signaling studies may also help understand molecular mechanisms of other AMPK-related diseases (Significance and Impact).

黏液蛋白是黏液中的一种主要蛋白成分，在粘膜先天防御中起着至关重要的作用