Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss in children. Inflammation is a hallmark of OM. Although appropriate inflammatory response triggered by bacteria is essential for eradicating bacterial pathogen, excessive inflammatory response is clearly detrimental to the host due to severe tissue damage. To avoid overactive and detrimental inflammatory response, inflammation must be tightly regulated. Bacteria-induced negative feedback regulation is thought to play a critical role in preventing overactive inflammatory response by inhibiting Toll- like receptor-dependent signaling adaptors. However, the molecular mechanisms underlying the negative feedback regulation of inflammation in the pathogenesis of OM remain unknown. Our Long-term Objective is to understand the molecular mechanisms by which inflammation is induced and regulated in the pathogenesis of OM. During the previous grant period, we focused on investigating the key positive signaling pathways involved in induction of NF-kB-dependent inflammatory response by OM bacterial pathogens including NTHi and S. pneumoniae. Recently we found that CYLD, a newly identified novel deubiquitinase, acts as a negative regulator for NF-kB-dependent inflammatory response induced by NTHi in an autoregulatory feedback manner. Interestingly, CYLD is expressed at low level in middle ear under physiological conditions, but is greatly up-regulated by NTHi. These encouraging preliminary results have thus laid a solid foundation for us to fully investigate the negative feedback regulatory mechanisms by which NTHi-induced NF-kB-dependent inflammation is tightly controlled by CYLD in the pathogenesis of OM in vitro and in vivo (Hypothesis & Short-term Objective).
Aim 1. Determine the key receptor-dependent signaling adaptors required for mediating NTHi-induced NF-kB-dependent inflammatory response.
Aim 2. Determine the molecular mechanism by which CYLD inhibits NTHi-induced NF-kB-dependent inflammatory response via negative cross-talk with the TRAF6/7 adaptor complex.
Aim 3. Determine the molecular mechanisms by which CYLD is induced and regulated by NTHi. Overall, the proposed studies will provide novel insights into the molecular mechanism underlying the tight regulation of inflammation in OM and may lead to new therapeutic strategies for OM patients. ? ? ?

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Watson, Bracie
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University of Rochester
Schools of Dentistry
United States
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Zhang, Yi-Shuai; Li, Jian-Dong; Yan, Chen (2018) An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol 819:30-34
Konduru, Anuhya Sharma; Matsuyama, Shingo; Lee, Byung-Cheol et al. (2017) Curcumin Inhibits NTHi-Induced MUC5AC Mucin Overproduction in Otitis Media via Upregulation of MAPK Phosphatase MKP-1. Int J Inflam 2017:4525309
Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin et al. (2017) Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis. Cardiovasc Drugs Ther 31:157-166
Harusato, A; Abo, H; Ngo, V L et al. (2017) IL-36? signaling controls the induced regulatory T cell-Th9 cell balance via NF?B activation and STAT transcription factors. Mucosal Immunol 10:1455-1467
Lin, Jizhen; Hafrén, Lena; Kerschner, Joseph et al. (2017) Panel 3: Genetics and Precision Medicine of Otitis Media. Otolaryngol Head Neck Surg 156:S41-S50
Raji, Idris; Yadudu, Fatima; Janeira, Emily et al. (2017) Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase. Bioorg Med Chem 25:1202-1218
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
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
Konduru, Anuhya S; Lee, Byung-Cheol; Li, Jian-Dong (2016) Curcumin suppresses NTHi-induced CXCL5 expression via inhibition of positive IKK? pathway and up-regulation of negative MKP-1 pathway. Sci Rep 6:31695
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

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