Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss in children. Mucus overproduction is a hallmark of OM. S. pneumoniae (Sp) is the most common Gram-positive bacteria causing OM. Currently available vaccines have limited serotype coverage and antibiotic treatment contributes to the emergence of antibiotic-resistance. Thus, developing alternative novel therapeutic strategies is urgently needed for controlling mucus overproduction in OM based on investigating and identifying the key molecular therapeutic targets, which, however, remain unidentified (innovation). The long-term goal is to understand the molecular mechanisms by which mucin, the major protein component of mucus, is up-regulated so that the potential therapeutic targets can be identified. During previous grant period, we found that Sp up-regulates MUC5AC mucin via activation of MAPK ERK;ERK activation also leads to induction of MKP-1, which in turn inhibits ERK and thereby acts as a negative feedback regulator for ERK-dependent MUC5AC induction. Increasing expression of negative regulators such as MKP-1 has long been thought as attractive therapeutic strategy for treating overactive host response, without causing serious adverse effects. Interestingly, our preliminary studies indicate that MKP-1 itself is further negatively controlled by phosphodiesterase 4B (PDE4B);Rolipram, a specific inhibitor of PDE4 that has been already in late phase III clinical trial for asthma and COPD, potently inhibited Sp-induced mucin MUC5AC up-regulation and increased MKP-1 expression in vitro and in vivo. Moreover, PDE4B-siRNA inhibited MUC5AC induction in vitro. Further ototopical post-inoculation administration of general PDE inhibitor inhibited mucin MUC5AC up-regulation in a mouse OM model. Together, these exciting preliminary data suggest that Sp up-regulates mucin MUC5AC via activation of the positive ERK pathway and inhibition of the negative MKP-1 pathway. Thus, we hypothesized that PDE4B plays a critical role in Sp-induced MUC5AC up-regulation by inhibiting cAMP-PKA-dependent MKP-1 expression, and post-inoculation delivery of specific PDE4B inhibitor will effectively inhibit MUC5AC induction. We will test our hypothesis by investigating the molecular mechanisms by which PDE4B regulates Sp-induced MUC5AC up-regulation and evaluate the therapeutic effects of PDE4B inhibitor on mucus overproduction in OM (short-term goal).
Our specific aims are:
Aim 1. Determine if PDE4B is required for regulating Sp-induced MUC5AC up-regulation in vitro and vivo.
Aim 2. Determine the molecular mechanism by which PDE4B regulates MUC5AC up-regulation in vitro and in vivo.
Aim 3. Determine the therapeutic effect of post-inoculation administration of specific PDE4 inhibitor on inhibiting MUC5AC induction in vivo. Overall, these studies will unveil novel molecular mechanisms underlying mucin up-regulation and identify novel therapeutic targets, leading to new therapeutic strategy for inhibiting mucus overproduction in OM (significance).
Otitis media (OM) 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 mainly caused by mucus overproduction, the hallmark of OM. Currently available vaccines have limited serotype coverage and antibiotic treatment contributes to the emergence of antibiotic-resistance and thus developing alternative novel therapeutic strategies is urgently needed for controlling mucus overproduction in OM based on investigating and identifying the key molecular therapeutic targets. The currently proposed studies will advance our understanding of molecular mechanisms underlying mucin up-regulation and identify novel therapeutic targets, leading to new therapeutic strategy for inhibiting mucus overproduction in OM.
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