Regulation of tissue oxygenation in the ocular lens

描述（由申请人提供）：年龄相关性核性白内障被认为至少部分是由累积的氧化损伤引起的。本文探讨了分子氧在这一过程中的作用。使用一种新型的光电系统，氧气在人类和牛镜片内的分布将被测量为温度和外部pO2的函数。由此产生的氧图将定量地与组织内的氧消耗有关，并用于计算透镜内氧的有效扩散系数。将评估线粒体和非线粒体耗氧对维持晶状体核心缺氧的相对贡献，并在坏血病动物模型中直接测试抗坏血酸氧化作为耗氧过程的作用。将确定老化的人类和动物晶状体是否消耗更少的氧气，因此，氧气是否积聚在这些晶状体的核心。大多数接受玻璃体切除手术的患者在手术后12个月内发生核性白内障。我们推测这是由于在手术过程中氧气淹没了通常缺氧的晶状体核心。为了验证是否存在这种情况，将在兔模型玻璃体切除手术期间监测晶状体pO2。最后，初步数据表明纤维细胞分化发生在一个陡峭的氧梯度。随着分化的进行，细胞经历了从有氧状态到厌氧状态的深刻代谢转变。我们已经开发了一个小鼠晶状体器官培养系统，这将使我们能够研究缺氧对分化纤维细胞基因表达模式的影响。

DESCRIPTION (provided by applicant): 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.