Fred A. Pereira, Ph.D.
Huffington Center on Aging
Departments of Otolaryngology–Head and Neck Surgery and Molecular and Cellular Biology
Interdepartmental Program in Cell and Molecular Biology
Ph.D.: University of Manitoba, Winnipeg, Canada
Postdoctoral training: Baylor College of Medicine, Houston
Signaling Pathways in Auditory Development, Aging and Cancer
Our long-term goal is to enhance, protect, repair or regenerate hair cells, supporting cells and associated nerves in the mammalian hearing organ and neurons in the auditory cortex that are loss with age (development or aging) or due to noise, trauma and chemotherapeutic insults. We aim to identify molecules and their signaling pathways that modulate inner ear and brain cell function.
Deafness is a relatively common disorder, with approximately 1 in 1000 children born with a serious permanent hearing impairment, single gene defects account for over half of the cases of childhood deafness. The World Health Organization (WHO) estimated hearing loss and deafness affected at least 250 million people worldwide in 2002 and is an increasing challenge to public health as lifespan increases and the general population ages.
We have identified gene-signaling pathways important for development, aging and regeneration of hair cells and auditory neurons. We discovered that loss of the orphan nuclear receptor NR2F1 results in the production of extra hair cells and supporting cells (a stem cell pool) and changes in cortical neurogenesis. We are characterizing the signaling pathways NR2F1 regulates by performing biochemical, molecular, bioinformatic and computational, and transcriptome (chromatin boundaries and structure, epigenetic and transcriptional regulation of gene expression) analyses. One pathway involves circadian rhythms; a diurnal (24h) molecular clock that controls the synchronization of gene functions in response to environmental and cellular cues. We are characterizing how circadian rhythms regulate the development, aging and regeneration of hair cells and neurons at the molecular and organ level. Findings from these studies will help us to develop therapies to regenerate and/or protect aging hair cells and neurons.
We also investigate the structure and function of a novel membrane motor protein, SLC26A5 prestin (quick tempo protein) in outer hair cells (OHC). Prestin is responsible for the active feedback mechanism required for amplifying and selecting high frequency hearing, which is preferentially reduced with age. We discovered that prestin is localized in membrane microdomains or rafts and that changes in membrane cholesterol disrupts OHC functions. Indeed, humans that are dyslipidemic have reduced hearing abilities and we found that cholesterol is able to modulate and tune prestin activity and the hair cell motor for hearing. Studies are directed to understanding the mechanisms of prestin and OHC function with increasing age and in altered cholesterol environments.
The wildly used platinum chemotherapy agents, cisplatin and carboplatin, cause hearing loss in a broad spectrum of cancer patients, and with at least 60% of pediatric patients affected. Currently no pharmacologic agents have US Food and Drug Administration approval to prevent or reverse platinum-induced hearing loss. Activated platinum ototoxicity initially impairs high frequency hearing and progresses to lower frequencies with increasing cumulative dosing. The progressive, irreversible side effects of platinum agents greatly impair the quality of life and frequently result in lowered dosing or discontinuation. Interventions to reduce platinum ototoxicity and hearing loss while maintaining dose intensity or allowing dose escalation, without interfering with tumoricidal effects are urgently needed. Platinum compromises mitochondria to initiate apoptosis and produces toxic levels of reactive oxygen species (ROS) leading to cell death of sensory and non-sensory cochlear structures. We are developing otoprotection strategies aimed at decreasing ROS in animal model experiments to determine dosing, delivery route and treatment post platinum therapy for reduction in oxidative damage, ototoxicity and hearing loss.
Our studies hope to provide insights into understanding human disorders of auditory and neuronal function and to develop pharmacologic, gene or cell-based therapy to improve the quality of life during aging and cancer.
- Somma et al. (2012). Head bobber: an insertional mutation on chromosome 7 causes inner ear patterning defects, hyperactive circling and deafness. J. Assoc. Res. Otolaryngol. Jun;13(3):335-49 PMID 22383091.
- Montemayor et al. (2010). Genome-wide analysis of binding sites and direct target genes of the orphan nuclear receptor NR2F1/COUP-TFI. PLoS ONE 5(1): e8910. PMID: 20111703
- Rajagopalan et al. (2009). Glycosylation regulates prestin cellular activity. J. Assoc. Res. Otolaryn. 11(1):39-51. PMCID: 19898896
- McGuire et al. (2009). Cysteine mutagenesis reveals transmembrane residues associated with charge translocation in prestin. J. Biol. Chem. 285(5):3103-13 PMID: 19926791
- Minor et al. (2009). DNA sequence analysis of SLC26A5, encoding prestin, in a patient-control cohort: identification of fourteen novel DNA sequence variations. PLoS ONE 4(6):e5762. PMCID: PMC2686157
- Sfondouris et al. (2008). Membrane composition modulates prestin-associated charge movement. Journal of Biol. Chem. 283(33):22473-8. PMCID2504877
- Sturm et al. (2007). Functional expression and microdomain localization of prestin in cultured cells. Otolaryn. Head & Neck Surgery 136: 434-439. PMC2679365
- Rajagopalan et al. (2007) .Tuning of the outer hair cell motor by membrane cholesterol. J. of Biol. Chem., 282 (50): 36659-36670. PMC2679373
- Tang et al. (2006). COUP-TFI controls Notch regulation of hair cell and support cell differentiation. Development 133: 3683-3693. PMID: 16914494
- Rajagopalan et al. (2006). Essential helix interactions in the anion transporter domain of prestin revealed by evolutionary trace analysis. J. Neuroscience 26(49):12727-12734. PMC2675645