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An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss in Homozygous Foxo3-knockout Mice - PhD Thesis Defense

Holly Beaulac - PhD Candidate
Advisor: Pat White, PhD

Approximately 16% of global cases of adult-onset hearing loss are attributable to excessive, occupational noise exposure. The prevalence of noise-induced hearing loss (NIHL) continues to increase with limited therapeutic options available. By studying the underlying pathology of NIHL using genetic loss-of-function models, it is possible to identify genes that contribute to hearing loss susceptibility. FOXO3 is a forkhead transcription factor involved in several cellular processes including growth, survival, stress resistance, apoptosis, and longevity. My lab has previously established a role for FOXO3 in preserving outer hair cells (OHCs) and hearing thresholds following a mild noise exposure in mice. I hypothesized that in the absence of FOXO3, reactive oxygen species would accumulate in response to noise exposure and lead to OHC apoptosis. I analyzed the immediate effect of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo+/KO), and Foxo3 knock-out (Foxo3KO/KO) FVB mice. Well-characterized components of noise-induced damage including calcium regulation, oxidative stress, inflammation, apoptosis, necrosis, and parthanatos were examined. In the Foxo3KO/KO mouse, dynamic immunoreactive modulation of the calcium buffer oncomodulin was correlated with OHC loss beginning 4 hours post-noise exposure. Parthanatos was identified as the main cell death pathway for OHCs. In opposition to my hypothesis, oxidative stress response pathways were not significantly altered. Using RNA sequencing I identified differentially expressed genes and examined one whose role in the cochlea has not been described. Glycerophosphodiester Phosphodiesterase Domain Containing 3 (GDPD3) is a possible source of Lysophosphatidic acid (LPA). LPA has been demonstrated to prevent OHC loss after severe noise exposure. When I treated noise-exposed animals with LPA, immediate OHC damage was reduced but no long-term prevention of cell death and hearing loss was observed. These data suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, in part through interaction with GDPD3 to help sustain endogenous LPA levels. Continuing work includes examining FOXO3’s cell-specific importance and recapitulating the NIHL susceptibility linked to human single nucleotide polymorphisms (SNPs) associated with increased FOXO3 levels.

 Apr 26, 2021 @ 10:00 a.m.

Host: Univ. Rochester School of Medicine and Dentistry
The Neuroscience Graduate Program

The role of microglial β2 adrenergic signaling in Alzheimer's disease pathology - PhD Thesis Proposal

Linh Le - PhD Candidate
Advisors: Ania Majewska, PhD and Kerry O'Banion, MD, PhD

 May 07, 2021 @ 1:00 p.m.