Otitis media (OM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Inflammation is a hallmark of OM. Developing highly effective vaccines still remains a great challenge. Inappropriate antibiotic treatment increased antibiotic resistance substantially. Currently, there are no effective therapeutics including anti-inflammatory agents available for OM due to poor understanding of the pathogenic mechanism underlying inflammation and the effective therapeutic targets. Although appropriate inflammation is essential for eradicating pathogens, excessive inflammation is clearly detrimental to the host. Thus, inflammation must be tightly regulated. However, how inflammation is tightly regulated remains unknown. Our long-term objective is to understand the molecular mechanisms by which inflammation is tightly regulated in OM and to identify effective therapeutic targets. During previous grant period, we identified a novel deubiquitinase CYLD as the key negative regulator for tightly controlling NTHi bacteria-induced inflammation in OM. In view of the past effort in developing anti-inflammatory agents, most strategies have focused on directly targeting the positive pathways, e.g., the I?B kinase (IKK), to suppress inflammation. While these agents often showed reasonable efficacy, they did exhibit significant adverse effects, e.g., increased susceptibility to infection and apoptosis, which prevented their further clinical use. Thus, we hypothesized that up-regulating CYLD, the key negative regulator of inflammation, by pharmacological inhibition of its own negative regulator, may represent a novel and advantageous anti-inflammatory strategy for treating overactive inflammation in OM without causing serious adverse effects often seen with targeting positive regulator of inflammation (hypothesis &innovation). Indeed, our preliminary studies demonstrate that CYLD itself is further negatively controlled by PDE4;Pharmacological inhibition of PDE4 led to the suppression of inflammation by up-regulating CYLD expression likely via JNK. These preliminary data have thus laid a solid foundation for us to investigate the molecular mechanisms underlying negative regulation of CYLD by PDE4B-JNK2 pathway and evaluate the therapeutic effect of up-regulating CYLD by inhibiting its own negative regulator in NTHi-induced inflammation in OM (short-term objective).
Our specific aims are:
Aim 1. Determine if PDE4B is critical for mediating NTHi-induced inflammation by inhibiting CYLD in vitro &in vivo.
Aim 2. Determine how PDE4B regulates NTHi-induced inflammation by inhibiting CYLD via selective activation of JNK2 in vitro &in vivo.
Aim 3. Determine the therapeutic effect of PDE4B inhibition on NTHi-induced inflammation in a mouse OM model. Overall, the proposed studies will advance our understanding of molecular pathogenesis of OM and lead to identifying novel therapeutic targets and new anti-inflammatory agents for OM.

Public Health Relevance

Otitis media (OM), inflammation of middle ear, is the most common childhood bacterial infection, accounting for 24.5 million visits and costing over $5 billion annually, and is also the leading cause of conductive hearing loss in children. Developing highly effective OM vaccines still remains a great challenge, inappropriate antibiotic treatment increased antibiotic resistance substantially and currently there are no effective therapeutics including anti-inflammatory agents available for OM due to poor understanding of the pathogenic mechanism underlying inflammation and the effective therapeutic targets. The currently proposed studies will advance our understanding of molecular pathogenesis of OM and lead to the identification of novel therapeutic targets and development of new anti-inflammatory therapeutic strategy for inhibiting inflammation in OM.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005843-15
Application #
8704402
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Watson, Bracie
Project Start
2002-09-20
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia State University
Department
Type
Organized Research Units
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Lee, Byung-Cheol; Miyata, Masanori; Lim, Jae Hyang et al. (2016) Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88. Proc Natl Acad Sci U S A 113:E165-71
Andrews, Carla S; Matsuyama, Shingo; Lee, Byung-Cheol et al. (2016) Resveratrol suppresses NTHi-induced inflammation via up-regulation of the negative regulator MyD88 short. Sci Rep 6:34445
Konduru, Anuhya S; Lee, Byung-Cheol; Li, Jian-Dong (2016) Curcumin suppresses NTHi-induced CXCL5 expression via inhibition of positive IKKβ pathway and up-regulation of negative MKP-1 pathway. Sci Rep 6:31695
Susuki-Miyata, Seiko; Miyata, Masanori; Lee, Byung-Cheol et al. (2015) Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. Proc Natl Acad Sci U S A 112:E1800-9
Miyata, Masanori; Lee, Ji-Yun; Susuki-Miyata, Seiko et al. (2015) Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M. Nat Commun 6:6062
Tapadar, Subhasish; Fathi, Shaghayegh; Raji, Idris et al. (2015) A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities. Bioorg Med Chem 23:7543-64
Andrews, Carla S; Miyata, Masanori; Susuki-Miyata, Seiko et al. (2015) Nontypeable Haemophilus influenzae-Induced MyD88 Short Expression Is Regulated by Positive IKKβ and CREB Pathways and Negative ERK1/2 Pathway. PLoS One 10:e0144840
Lee, Ji-Yun; Komatsu, Kensei; Lee, Byung-Cheol et al. (2015) Vinpocetine inhibits Streptococcus pneumoniae-induced upregulation of mucin MUC5AC expression via induction of MKP-1 phosphatase in the pathogenesis of otitis media. J Immunol 194:5990-8
Statt, Sarah; Ruan, Jhen-Wei; Hung, Li-Yin et al. (2015) Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells. Am J Respir Cell Mol Biol 53:689-702
Wang, Wenzhuo Y; Komatsu, Kensei; Huang, Yuxian et al. (2014) CYLD negatively regulates nontypeable Haemophilus influenzae-induced IL-8 expression via phosphatase MKP-1-dependent inhibition of ERK. PLoS One 9:e112516

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