Pharmacologic Regulation of Auditory Hair Cell Regeneration
Abstract
Hearing loss is one of the most common chronic conditions affecting individuals of all ages, ethnicities, and genders. Whether sudden or gradual, loss of hearing can affect the quality of life, restrict employment and job performance, limit recreational and social activities, compromise safety by hindering an individual s ability to respond to alarms and warning signs, and lead to depression and social isolation. Hearing loss is generally associated with trauma and degeneration of the sensory hair cells of the inner ear. Humans are born with a limited number of sensory hair cells. Consequently, the loss of those cells is always permanent and cannot be naturally repaired. In non-mammalian, non-human vertebrates (e.g., fish, birds, reptiles, and amphibians), loss of sensory hair cells is compensated by (1) direct transdifferentiation, a process through which a sensory hair cell s supporting cell transforms itself into a new sensory hair cell; or (2) growth and division of existing supporting cells into new hair cells and new supporting cells. Laboratory experiments have demonstrated that auditory supporting cells in some mammals can divide and generate new hair cells through genetic manipulation. The supporting cells ability to divide and generate new cells is controlled by different genes. Among those are the inducible transcription factor Nuclear-factor-kappa B (NF-kB), the cell division regulator Cyclin D1 (CycD1), and the downstream cell division inhibitor Retinoblastoma (RB) gene family. Manipulation of any of these three groups of genes is known to induce the formation of new supporting cells and hair cells in the inner ear and other systems. However, most methods available to control these genes expression are limited and not suitable for clinical interventions. Our laboratory has recently identified a chemical compound that affects the expression of the three genes mentioned above by activating expression of the NF-kB, which in turn triggers CycD1 expression and removes the inhibitory effect of the RB genes. Early experiments have shown that treatment of cultured cells or animals with such compound results on cell proliferation and generation of new cells, which in all aspects tested so far, behave similarly to a regular sensory hair cell. As such, the present study has been designed to test the overall hypothesis that pharmacologic cell cycle regulation of auditory supporting cells will enable hair cell regeneration and lead to hearing restoration. To test such a hypothesis, we will use medicinal chemistry to allow us to further explore the regenerative properties of such a compound and improve its effectiveness to treat and prevent hearing loss (Specific Aim 1). It is well-known that a drug s efficacy can be significantly impacted by how it is delivered. Testing alternative delivery systems for our drug of interest will allow for better control of its pharmacologic properties, toxicity, immunogenicity, and efficacy while improving and targeting its performance to the cochlea (Specific Aim 2). Our preliminary tests so far support our research idea and our chances to successfully improve our current formulation and identify an improved version of our compound, which will be suitable for further preclinical and clinical trials. Currently, 15% of adults in the United States, ages 18-64, and 28% of people ages 65 and older have some level of hearing impairment, varying from moderate to complete deafness in one or both ears. Likewise, consistent with the complexity of their job, the prevalence of hearing loss and tinnitus in the military population is greater than in the general public. For many years, tinnitus, the perception of sound or ringing in the ears, and hearing loss topped the list as the two most prevalent service-related disabilities for Veterans in the U.S. Conservative estimates by the American Academy of Audiology and the House Committee on Veterans Affairs show that approximately 21% of U.S. Army Vete
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010789
Entities
People
- Sonia Rocha-sanchez
Organizations
- Creighton University
- United States Army