Regulation of tissue oxygenation in the ocular lens

描述（由申请人提供）：据信，视网膜相关核性白内障至少部分由累积的氧化损伤引起。该提议探讨了分子氧在这一过程中的作用。使用一种新的光电管系统，人体和牛晶状体内的氧分布将被测量为温度和外部pO2的函数。所得到的氧气图将与组织内的氧气消耗定量相关，并用于计算透镜内的氧气有效扩散系数。将评价线粒体和非线粒体氧消耗对维持透镜核心缺氧的相对贡献，并将在坏血病动物模型中直接测试抗坏血酸氧化作为氧消耗过程的作用。将确定老化的人类和动物晶状体是否消耗较少的氧，并且因此确定氧是否积聚在这种晶状体的核心中。大多数接受玻璃体切除术的患者在手术后12个月内发生核性白内障。我们假设这是由于手术过程中氧气淹没了透镜的缺氧核心。为了测试是否是这种情况，将在兔模型的玻璃体切除术期间监测透镜pO2。最后，初步的数据表明，纤维细胞分化发生在陡峭的氧气梯度。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。我们已经开发了一个小鼠透镜器官培养系统，这将使我们能够调查缺氧对分化中的纤维细胞的基因表达模式的影响。 总的来说，这些实验将为分子氧在白内障病因学和正常透镜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.