Sheep as a large animal model for hearing research: comparison to common laboratory animals and humans

Abstract Sensorineural hearing loss (SNHL), caused by pathology in the cochlea, is the most common type of hearing loss in humans. It is generally irreversible with very few effective pharmacological treatments available to prevent the degenerative changes or minimise the impact. Part of this has been attributed to difficulty of translating “proof-of-concept” for novel treatments established in small animal models to human therapies. There is an increasing interest in the use of sheep as a large animal model. In this article, we review the small and large animal models used in pre-clinical hearing research such as mice, rats, chinchilla, guinea pig, rabbit, cat, monkey, dog, pig, and sheep to humans, and compare the physiology, inner ear anatomy, and some of their use as model systems for SNHL, including cochlear implantation surgeries. Sheep have similar cochlear anatomy, auditory threshold, neonatal auditory system development, adult and infant body size, and number of birth as humans. Based on these comparisons, we suggest that sheep are well-suited as a potential translational animal model that bridges the gap between rodent model research to the clinical use in humans. This is especially in areas looking at changes across the life-course or in specific areas of experimental investigation such as cochlear implantation and other surgical procedures, biomedical device development and age-related sensorineural hearing loss research. Combined use of small animals for research that require higher throughput and genetic modification and large animals for medical translation could greatly accelerate the overall translation of basic research in the field of auditory neuroscience from bench to clinic

Redox Homeostasis in Ocular Tissues: Circadian Regulation of Glutathione in the Lens?

Accumulating evidence in tissues suggests an interconnection between circadian clocks and redox regulation. Diurnal variations in antioxidant levels, circadian rhythms of antioxidant enzyme activity, and differences in oxidative stress markers at different times of the day all indicate that oxidative stress responses follow a circadian rhythm. Disruptions of circadian rhythms are linked to a number of age-related diseases, including those in the eye. Typically, ocular tissues contain a robust antioxidant defence system to maintain redox balance and minimise oxidative stress and damage. The lens, in particular, contains remarkably high levels of the antioxidant glutathione (GSH). However, with advancing age, GSH levels deplete, initiating a chain of biochemical events that ultimately result in protein aggregation, light scattering, and age-related cataracts. While there is evidence that the lens exhibits circadian rhythms in the synthesis and release of melatonin, little is known about the regulation or function of timekeeping mechanisms in the lens. Since circadian rhythms are disrupted with age, and the depletion of GSH in the lens is a known initiating factor in the development of age-related cataracts, understanding the mechanisms involved in regulating GSH levels may lead to the future development of approaches to manipulate the clock to restore GSH levels and redox balance in the lens, and protect the lens from cataracts

Molecular and functional mapping of regional differences in P2Y receptor expression in the rat lens

Extracellular ATP has been shown to mobilize intracellular Ca2+ in cultured ovine lens epithelial cells and in human lens epithelium, suggesting a role for purines in the modulation of lens transparency. In this study, we characterized the expression profiles of P2Y receptor isoforms throughout the rat lens at both the molecular and the functional levels. RT-PCR indicated that P2Y1, P2Y2, P2Y4 and P2Y6 are expressed in the lens, while P2Y12, P2Y13 and P2Y14 are not. Immunohistochemistry, using isoform specific antibodies, indicated that the epithelium does not express P2Y1 and P2Y2, but that the underlying fiber cells, which differentiate from the epithelial cells, exhibit strong membranous labeling. Although co-expressed in fiber cells, differences in P2Y1 and P2Y2 expression were apparent. P2Y1 expression extended deeper into the lens than P2Y2, and its expression co-localized with Cx50 gap junction plaques, while P2Y2 did not. Labeling for P2Y4 and P2Y6 receptors were observed in both epithelial cells and fiber cells, but the labeling was predominantly cytoplasmic in nature. While purine agonist (ATP, ADP, UTP and UDP) application to the lens induced mobilization of intracellular Ca2+ in cortical fiber cells, little to no effect was observed in the anterior and equatorial epithelium. Thus the inability of UTP and UDP to mobilize intracellular Ca2+ in the epithelium and the predominately cytoplasmic location of P2Y4 and P2Y6 suggests that these receptors may represent an inactive pool of receptors that may be activated under non-physiological conditions. In contrast, our results indicated that P2Y1 and P2Y2 are functionally active in fiber cells and their differential subcellular expression patterns suggest they may regulate distinct processes in the lens under steady state conditions