Pilot Project Awardees

Gopal Jadhav

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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.

Andrew Wagner

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The vestibular system is responsible for sensing the complex head motions that occur during daily life. As a result, vestibular dysfunction can cause symptoms of dizziness, nausea, and/or unsteadiness during routine activities.  Relative to other causes of dizziness, vestibular dysfunction leads to a greater decline in quality of life and a higher utilization of medical resources. Due to the considerable variability in clinical presentations, personalized rehabilitation strategies are needed to address the symptoms of chronic vestibular dysfunction. This pilot project aims to facilitate the development of personalized vestibular therapies by testing the feasibility of using a novel vestibular assessment to define specific targets for vestibular rehabilitation in patients with chronic vestibular dysfunction. To accomplish this goal, we will leverage several recent scientific and technical advances that together allow us to administer an efficient, comprehensive, and specific battery of vestibular tests. This includes measuring each individual aspect of the human vestibular system (semicircular canals, otolith organs, central canal-otolith integration) using each of three distinct vestibular modalities (gaze stability, postural control, and spatial orientation). The long-term goal for this pilot project is to inform future, larger scale projects that aim to (1) define targets for personalized rehabilitation, (2) establish “functional vestibular phenotypes” based upon patterns of physiological impairment, and (3) parse the specific effects of aminoglycoside exposure on the human vestibular system throughout the lifespan. 

Oleg Korzyukov

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Age-related neurodegeneration is a devastating brain condition, manifesting in the deterioration of essential cognitive functions such as auditory processing. Central auditory processing relies on the transmission of information from the brainstem to cortical neuronal populations and involves the interplay between networks distributed across temporal and frontal lobes. Neurodegeneration affecting these auditory networks is a significant factor contributing to age-related neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease (AD).

Central auditory processing networks become functionally integrated in different configurations depending on the ongoing tasks, such as passive listening or auditory-controlled voice production. Thus, neurodegeneration-related aberrations in these networks may give rise to disease-specific bioelectrical brain indices that can help disentangle multiple neurodegenerative processes. Understanding the mechanisms behind these processes is crucial for proposing appropriate clinical interventions.

The long-term goal of this research is to identify and functionally characterize disease-specific bioelectrical markers associated with age-related neurodegeneration that impacts auditory processing within temporal and frontal brain neuronal networks during passive listening and voice production tasks. Our approach aims to develop and validate bioelectrical brain markers that will help identify individuals at heightened risk of AD and/or cognitive impairment, potentially before clinical symptoms appear. Furthermore, characterizing these disease-specific bioelectrical indices in PD during auditory processing will assist in distinguishing between different neurodegenerative processes, leading to earlier diagnosis and more effective management.

Using Magnetoencephalography (MEG) and Electroencephalography (EEG), we will study the timing and brain localization of neuronal activity elicited during various stages of auditory processing. This approach can help probe the neurodegenerative status of neuronal populations contributing to auditory function. We hypothesize that measurable neurodegenerative effects in the frontal and temporal cortical areas involved in auditory processing can serve as disease-specific biomarkers for neurodegenerative processes in AD and PD.

Sarath Vijayakumar

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder with a prevalence of over 40,000 children and adults in the U.S. and an estimated 105,000 people worldwide. It is the most common fatal genetic disease in the United States. The reduced or null function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein predisposes patients to frequent pulmonary bacterial infections, pancreatic exocrine insufficiency, and gastrointestinal complications. Although the arsenal of antibiotics has expanded, aminoglycosides, especially tobramycin—selected for its anti-P. aeruginosa activity—remain pivotal for managing acute pulmonary exacerbations in patients with CF. Notably, while many aminoglycosides manifest ototoxic effects predominantly either in the cochlea or the vestibular system, tobramycin impacts both systems. In the inner ear, CFTR expression has been observed in the basolateral membrane of the cochlear outer hair cells and it has been shown to interact directly with prestin, the cochlear outer hair cell electromotility protein. Furthermore, pendrin and CFTR mRNA transcripts co-localize in the mitochondria-rich cells of the mouse endolymphatic sac. While CFTR's role in vestibular physiology has been implied, its exact expression pattern within the vestibular organs remains elusive. In this proposed study, we postulate: 1) the higher incidence of vestibular impairment in patients with CF is due to CFTR mutation affecting the ionic homeostasis and normal function of the vestibular organs 2) CFTR channel dysfunction sensitizes the vestibular organs to aminoglycoside ototoxicity. Our investigative approach will involve 1) mapping the cellular distribution of the CFTR channel across both vestibular and auditory organs, and 2) detailing the vestibular and auditory effects of tobramycin-induced ototoxicity using a CF mouse model harboring the prevalent CFTR ΔF508 mutation. This investigation aims to enrich our comprehension of the CFTR channel's physiological role in vestibular and auditory organs. From a public health perspective, this research would elucidate molecular underpinnings and associated risks of irreversible ototoxicity in CF patients undergoing tobramycin therapy.