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Principal Investigator: Jian-Dong Li
Organization: GEORGIA STATE UNIVERSITY
Fiscal Year: 2024
Award: $460,120
Funding agency: National Institute on Deafness and Other Communication Disorders
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).
Terms: <ATP-protein phosphotransferase><Accounting><Acute><Adenosine><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Autoregulation><Bacterial Infections><Cell Communication and Signaling><Cell Signaling><Childhood><Chronic><Clinical><Communicable Diseases><Conductive Deafness><Conductive hearing loss><D pneumoniae><D. pneumoniae><Data><Development><Diplococcus pneumoniae><Disease><Disorder><Down-Regulation><Economic Burden><Epithelial Cells><Foundations><Goals><Health><Homeostasis><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Intracellular Communication and Signaling><Kinase Family Gene><L-Lysine><L-Threonine><Link><Lung infections><Lysine><MG1><MUC5AC><MUC5AC gene><MUC5B><MUC5B gene><Mediating><Metabolic Protein Degradation><Miscellaneous Antibiotic><Molecular><Mucins><Mucociliary Clearance><Mucociliary Transport><Mucosa><Mucosal Immune Responses><Mucosal Tissue><Mucous Membrane><Mucous body substance><Mucus><Mucus Glycoprotein><Obstruction><Otitis Media><Pathogenesis><Pathogenicity Factors><Phosphorylation><Physiological Homeostasis><Play><Pneumococcus><Polyubiquitination><Production><Protein Kinase><Protein Phosphorylation><Protein Turnover><Proteins><Public Health><Regulation><Regulatory Protein Degradation><Resistance to antibiotics><Resistant to antibiotics><Respiratory Epithelium><Role><S pneumoniae><S. pneumoniae><Serotyping><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Streptococcus pneumoniae><Streptococcus pneumoniae plY protein><Structure of respiratory epithelium><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><Testing><Therapeutic><Therapeutic Agents><Threonine><Toll-Like Receptor 2><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Ubiquitilation><Ubiquitination><Ubiquitinoylation><Up-Regulation><Upregulation><Vaccines><Virulence Factors><Visit><access to vaccination><access to vaccines><airway epithelium><antibiotic drug resistance><antibiotic resistant><bacteria infection><bacteria pathogen><bacterial disease><bacterial disease treatment><bacterial infectious disease treatment><bacterial pathogen><biological signal transduction><childhood hearing loss><cost><de-ubiquitinase><de-ubiquitinating enzyme><defense response><developmental><early hearing loss><glycogen synthase a kinase><hearing loss in children><human disease><hydroxyalkyl protein kinase><innovate><innovation><innovative><microbe pathogen><microbial pathogen><middle ear><middle ear infection><mouse model><mucous><murine model><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><pathogen><pathogenic bacteria><pathogenic microbe><pediatric><pediatric hearing loss><phosphorylase b kinase kinase><physiological defense response><pneumolysin><protein degradation><pulmonary infections><respiratory tract epithelium><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><ubiquination><ubiquitin conjugation><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><vaccination access><vaccination availability><vaccine access><vaccine availability><virtual>