ACTIVATION OF THE HEXOSEMONOPHOSPHATE SHUNT IN THE LENS

此应用程序的广泛、长期目标是应用 对非手术治疗的拟议研究产生的结果 人类的渗透性-氧化性白内障。具体目标包括 单磷酸己糖分流四个不同方面的检查 晶状体中(HMPS)的激活：(A)量化HMPS和相关的 代谢活动；(B)调查#年的恢复过程 新陈代谢应激晶状体对HMPS活性、血糖和 磷代谢和离子转运；(C)测试甘露糖替代 葡萄糖作为糖酵解底物及其对多元醇途径的影响 活化和抗氧化性；以及(D)研究间接影响 生长因子对HMPS活性的影响。 实验模型包括(1)体内模型，如 链脲佐菌素糖尿病大鼠(胰岛素、醛糖还原酶治疗 抑制剂，或喂以甘露糖饮食)和喂食50%半乳糖的大鼠/兔，以及 (2)在渗透-氧化应激条件下，用动物(大鼠、 兔和豚鼠)晶状体和成人/婴儿晶状体。这些镜片 用体外核磁共振(核磁共振)波谱检查 辅以生化分析。 为了达到这一目的，首先，基础晶状体的代谢和它的 对代谢应激的反应和恢复进行了阐述。这个 然后，研究缓解这些压力的可能性，例如， 代谢调节，如用甘露糖代替葡萄糖。 同样，生长因子对HMPS激活的影响也是第一 评估后，将有可能修改镜片HMPS激活 保持NADPH和核糖磷酸在生物合成中的有效性 和抗氧化性。

The broad, long-term objective of this application is to apply findings generated from the proposed studies to the non-surgical treatment of human cataracts of osmotic-oxidative origin. The specific aims include the examination of four different aspects of hexose monophosphate shunt (HMPS) activation in the lens: (A) to quantify the HMPS and associated metabolic activities; (B) to investigate the recovery process in metabolically stressed lenses with regard to HMPS activity, glucose and phosphorus metabolism, and ionic transport; (C) to test mannose replacing glucose as the substrate of glycolysis and its effect on polyol pathway activation and oxidative resistance; and (D) to study the indirect effect of growth factors on the HMPS activity. Experimental models include (1) in-vivo models such as streptozotocin-diabetic rats (treated with insulin, aldose reductase inhibitors, or fed a mannose diet) and rats/rabbits fed 50% galactose, and (2) lens incubation under osmotic-oxidative stress using animal (rat, rabbit and Guinea pig) lenses and adult/infant human lenses. These lenses are examined with in-vitro nuclear magnetic resonance (NMR) spectroscopy supplemented with biochemical assays. To achieve the objective, first the basal lens metabolism and its response to and recovery from metabolic stresses are elucidated. The possibility of relieving these stresses is then examined, for example, with metabolic modulations such as the use of mannose to replace glucose. Similarly, the effect of growth factors on HMPS activation is first evaluated, after which, it will be possible to modify lens HMPS activation to maintain the availability of NADPH and ribose-Phosphate for biosynthesis and oxidative resistance.