Metabolic Modulation of Vision

描述（由申请人提供）：中央视觉为我们提供日常工作所必需的高敏锐度。然而，中央视觉对我们的代谢状态高度敏感：它在夜间和急性低血糖期间下降。短暂的中心暗点可出现在严重的低血糖症。急性低血糖的这些显著影响部分发生在视网膜中央。目前对慢性低血糖小鼠的分析表明，长期代谢应激降低视网膜敏感性，导致迟发性进行性变性。该提案将通过调查来研究视觉的代谢和昼夜调节，其根本原因和潜在后果：目的1：人类视觉的昼夜和代谢调节。目的2：猴视网膜葡萄糖利用和代谢调节。目的3：建立一种新的代谢应激性视网膜变性小鼠模型。目的1应用心理物理学（2 IFC）和生理学（mERG）技术研究非糖尿病患者和糖尿病患者视杆视和视锥视的昼夜节律和代谢调节。葡萄糖钳和一天中的时间将控制代谢状态。目的2通过测定猴视网膜mERG和t4 C-2-脱氧葡萄糖摄取，研究猴视网膜的代谢调节和葡萄糖利用。目的3研究胰高血糖素受体基因Gcgr无效突变的小鼠模型。视网膜的纯合子，而不是杂合子，慢慢失去敏感性和退化。将采用一系列行为解剖学、生理学、生物化学和分子技术研究迟发性进行性变性，以确定Gcgr-/-小鼠是否是进一步研究的适当模型。将测试补充饮食以拯救Gcgr-/-小鼠的视力。潜在的医疗益处是（1）改善人类中央视觉如何响应代谢应激的知识，（2）改善糖尿病患者关于过度使用胰岛素引起的暂时性中央视觉丧失的咨询，以及（3）用于研究某些类型的迟发性退行性视网膜疾病（如年龄相关性黄斑变性（AMD））的可能原因的新小鼠模型。

DESCRIPTION (provided by applicant): Central vision provides us high acuity essential for everyday tasks. However, central vision is highly sensitive to our metabolic state: it decreases at night and during acute hypoglycemia. Transient central scotomas can appear during severe hypoglycemia. These striking affects of acute hypoglycemia occur in part in central retina. Current analysis of a chronically hypoglycemic mouse indicates that long-term metabolic stress decreases retinal sensitivity causing late-onset progressive degeneration. This proposal will examine the metabolic and circadian modulation of vision, its underlying causes and potential consequences by investigating: Aim 1: Circadian and metabolic modulation of human vision. Aim 2: Glucose utilization and metabolic modulation in the monkey retina. Aim 3: A potential new mouse model for studying metabolic-stress induced retinal degeneration. Aim 1 studies the circadian and metabolic modulation of rod and cone vision of nondiabetics and diabetics using psychophysical (2IFC) and physiological (mERG) techniques. Glucose clamp and time of day will control metabolic state. Aim 2 studies metabolic modulation and glucose utilization in the monkey retina by measuring their mERG and retinal uptake of t 4C-2-deoxyglucose. Aim 3 will study a new mouse model made hypoglycemic by a null mutation in the glucagon receptor gene, Gcgr. Retinas of homozygotes, not heterozygotes, slowly loose sensitivity and degenerate. The late-onset, progressive degeneration will be studied with an array of behavioral anatomical, physiological, biochemical and molecular techniques to determine if the Gcgr-/- mouse is an appropriate model for further study. A supplemental diet will be tested for rescuing vision in Gcgr-/- mice. Potential medical benefits are (1) improved knowledge of how human central vision responds to metabolic stress, (2) improved counseling of diabetics about transient losses of central vision caused by over medication with insulin, and (3) a new mouse model for studying possible causes of some types of late-onset, degenerative retinal diseases such as age-related macular degeneration (AMD).