Regulation of tissue oxygenation in the ocular lens

描述(申请人提供)：年龄相关的核性白内障被认为至少部分是由累积的氧化损伤造成的。这项提议探讨了分子氧在这一过程中的作用。利用一种新的光电系统，将测量氧气在人和牛晶状体中的分布，作为温度和外部pO2的函数。由此得到的氧气图将与组织内的氧气消耗量定量相关，并用于计算氧气在晶状体内的有效扩散系数。将评估线粒体和非线粒体耗氧对维持晶状体核心低氧的相对贡献，并将直接在坏血酸动物模型中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较少的氧气，以及是否因此在这些晶状体的核心积累氧气。大多数接受玻璃体切除手术的患者在手术后12个月内发展为核性白内障。我们推测这是由于手术过程中，晶状体核心的氧气泛滥所致。为了测试这种情况是否属实，我们将在一个兔模型的玻璃体切除手术中监测晶状体的氧分压。最后，初步数据表明，纤维细胞分化发生在陡峭的氧气梯度上。随着分化的进行，细胞经历了从有氧状态到无氧状态的深刻代谢转变。我们已经开发了一种小鼠晶状体器官培养系统，该系统将使我们能够研究低氧对分化纤维细胞基因表达模式的影响。 总之，这些实验将为分子氧在白内障病因和正常晶状体生理学中的作用提供重要的新信息。

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.