ACTIVATION OF THE HEXOSEMONOPHOSPHATE SHUNT IN THE LENS

本申请的广泛、长期目标是应用 从拟定研究到非手术治疗产生的结果 人类白内障的病因。 具体目标包括 磷酸己糖分流四个方面的检查 透镜中的HMPS（HMPS）激活：（A）量化HMPS和相关的 代谢活动;（B）研究恢复过程 关于HMPS活性、葡萄糖和 磷代谢和离子转运;（C）测试甘露糖替代 葡萄糖作为糖酵解的底物及其对多元醇途径的影响 活化和抗氧化性;和（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，例如 链脲佐菌素糖尿病大鼠（用胰岛素、醛糖还原酶 抑制剂，或喂食甘露糖饮食）和喂食50%半乳糖的大鼠/兔，以及 (2)使用动物（大鼠， 兔和豚鼠）镜片和成人/婴儿人类镜片。 这些透镜 用体外核磁共振（NMR）光谱检查 并辅以生化分析。 为了实现该目标，首先是基础透镜代谢及其代谢产物。 阐明了对代谢应激的反应和从代谢应激中恢复。 的 缓解这些应力的可能性，然后检查，例如， 代谢调节，例如使用甘露糖代替葡萄糖。 类似地，生长因子对HMPS活化的作用首先是 评估后，可以修改透镜HMPS激活 维持NADPH和磷酸核糖的生物合成可用性 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.