Age-related nuclear cataract is believed to result, at least in part, from accumulated oxidative damage. This proposal explores the role of molecular oxygen in this process. Using a novel optode system, the distribution of oxygen within human and bovine lenses will be measured as a function of temperature and external pO2. The resulting oxygen maps will be related quantitatively to the consumption of oxygen within the tissue and used to calculate the effective diffusion coefficient of oxygen within the lens. The relative contributions of mitochondrial and non-mitochondrial oxygen consumption to the maintenance of hypoxia in the lens core will be evaluated and the role of ascorbate oxidation as an oxygen-consuming process will be tested directly in a scorbutic animal model. It will be determined whether aged human and animal lenses consume less oxygen and, as a result, whether oxygen accumulates in the core of such lenses. The majority of patients who undergo vitrectomy surgery develop nuclear cataracts within 12 months following the surgery. We hypothesize that this is due to oxygen flooding the normally hypoxic core of the lens during the surgical procedure. To test whether this is the case, lens pO2 will be monitored during vitrectomy surgery in a rabbit model. Finally, the preliminary data suggest that fiber cell differentiation occurs on a steep oxygen gradient. As differentiation proceeds, the cells undergo a profound metabolic shift from an aerobic to an anaerobic state. We have developed a mouse lens organ culture system that will allow us to investigate the effects of hypoxia on the pattern of gene expression in differentiating fiber cells. Collectively, these experiments will provide important new information on the role of molecular oxygen in the etiology of cataract and the physiology of the normal lens.
| McNulty, Richard; Wang, Huan; Mathias, Richard T et al. (2004) Regulation of tissue oxygen levels in the mammalian lens. J Physiol 559:883-98 |
