Pilot Project Awardees
Gopal Jadhav
Centers for Disease Control and Prevention (CDC) states noise induced hearing loss (NIHL) as one of the prevalent health issues in the U.S. Currently, there are no FDA approved treatments for NIHL. Therefore, search to identify novel druggable targets for NIHL is required. Recently, role of inflammation proved to be attractive targets for novel drug discovery against NIHL and associated ototoxicity. TREM1 is a main culprit responsible for exaggerating various inflammatory disorders by manipulating human immune system. Its pharmacological inhibition by LR12 in the subversion of various disease models, project that it might thus be used as a template to design TREM1 inhibitory agents, provided derivatives devoid mainly of proteolytic degradation and mutagenicity, could be discovered. Our preliminary data showed that TREM1 inhibition by LR12 protects against NIHL. To address LR12 low half-life issue, we identified two GJMs small molecules as potential TREM1 inhibitors using molecular docking. GJMs directly bind TREM1 and possibly with good PK/PD. Data together develops central hypothesis that "TREM1 inhibition as novel treatment against NIHL and associated ototoxicity". To achieve this, AIm (1) dual approach where GJMs/LR12/Vehicle will be administered trans-tympanically 1-day after (Therapeutic) or 1-week before (Prophylactic) exposure to PTS-noise levels. Hearing functions via ABRs and DPOAEs, and HCs, SGNs and macrophages abundance will be examined. We anticipate TREM1 inhibitors to attenuate NIHL. Aim (2) precise PK/PD of GJMs will be performed. We anticipate GJMs to be more stable, non-hepatotoxic and non-mutagenic than LR12. The data will allow us to determine the most efficacious and potent TREM1 inhibitor against NIHL and ototoxicity. Impact: Pilot studies will unwrap the critical role of TREM1 in NIHL and ototoxicity and display it as novel inflammatory target. TREM1 inhibition may preserve cochlear sensory cells. The data will reveal efficacy, potency, therapeutic window of protection against NIHL and PK/PD properties of GJMs. Such information will form the basis to prioritize lead TREM1 inhibitors (LR12/GJMs) for optimization of target selectivity and therapeutic ADMET properties to provide novel therapeutics for NIHL.