ESSENTIAL FATTY ACIDS AND RETINAL DEGENERATIONS

视杆外节（ROS）含有最高水平的多不饱和脂肪酸。 脂肪酸（PUFA）是身体中任何膜的脂肪酸。许多研究表明 ROS中的主要PUFA是二十二碳六烯酸（22：6 omega 3）， 对视网膜的正常功能很重要。饮食剥夺其 视网膜电图（ERG）的变化， 大鼠、灵长类动物和人类早产儿;灵长类动物的视力;以及 大鼠的亮度辨别学习。人类、狗和猫， 遗传性视网膜变性具有较低的22：6 ω 3血浆水平 比对照组。视网膜中22：6欧米茄3水平升高的大鼠 更容易受到光的伤害，而22：6的饮食限制 欧米伽3或其前体可防止光损伤。急性光损伤 导致ROS中22：6 ω 3的损失，表明22：6 ω 3的过氧化作用。 3可能是光损伤的一个因果因素。很明显，视网膜退化 玻璃体内注射Fe 2+后，22：6的过氧化反应是导致玻璃体内Fe 2+浓度升高的主要原因。 欧米伽3尝试改变大鼠ROS中的22：6 omega 3水平， 饮食剥夺仅导致22：6 Ω水平的微小变化， 3、在大多数其他身体器官显示出剧烈变化的情况下。 然而，在不同水平的周期性光照下饲养的大鼠表现出较大的变化 ROS 22：6 omega 3水平。这些独特的功能22：6欧米茄3在 视网膜，这是讨论整个建议，表明这一点， 脂肪酸对视网膜的正常结构和功能很重要。 此外，22：6欧米茄3代谢缺陷的建议， 遗传性视网膜变性使其变得更加重要， 研究这种脂肪酸的代谢。长期目标是 研究项目是确定22：6欧米茄3在正常和 患病的视网膜这个五年计划的具体目标是：1） 研究22：6 omega 3在遗传性视网膜变性中的作用， 微型贵宾犬和阿比西尼亚猫，2）确定的机制， 在必需脂肪酸作用期间大鼠视网膜中22：6 ω 3的保守性 缺乏，3）确定22：6欧米茄3在生化中的作用 大鼠视网膜对周期性光的适应与敏感性的关系 急性光损伤，以及慢性暴露于循环 不同强度的光，4）研究慢性 抗氧化剂的施用对视网膜对 急性持续光照刺激的损伤，以及慢性 暴露于不同强度的循环光，以及5）确定 延长和去饱和部位（视网膜与视网膜外）为22：6 欧米茄3脂肪酸和研究这些代谢过程。为了实现这些目标，A 提出了一系列体内和体外实验，其中 将详细研究22：6欧米伽3的代谢。的每个步骤 在形成22：6欧米伽3的延伸和去饱和途径将 在患有遗传性视网膜病变的狗和猫的视网膜和肝匀浆中进行测试， 视网膜变性大鼠将在omega 3-和/或 ω 6缺乏饮食和玻璃体内注射脂质前体， 为了研究22：6欧米伽3的生物化学机制。 类似的动物群将在明亮或昏暗的周期性光线下饲养， 确定膳食PUFA水平升高是否使他们更容易受到 光损伤。这些研究的结果将使我们更好地了解 22：6欧米伽3在视网膜中的代谢， 这种脂肪酸在视网膜变性中的作用。

Rod outer segments (ROS) contain the highest levels of polyunsaturated fatty acids (PUFA) of any membrane in the body. Many studies have shown that the major PUFA in ROS, docosahexaenoic acid (22:6 omega 3), is important to the normal function of the retina. Dietary deprivation of its essential precursors leads to changes in the electroretinogram (ERG) in rats, primates, and premature human infants; visual acuity in primates; and brightness discrimination learning in rats. Humans, dogs, and cats with inherited retinal degenerations have lower plasma levels of 22:6 omega 3 than controls. Rats with elevated levels of 22:6 omega 3 in their retinas are more susceptible to light damage, while dietary restriction of 22:6 omega 3 or its precursors protects against light damage. Acute light damage causes a loss of 22:6 omega 3 in ROS, suggesting peroxidation of 22:6 omega 3 may be a causal factor in light damage. Clearly, the retinal degeneration that follows intravitreal injection of Fe 2+ is due to peroxidation of 22:6 omega 3. Attempts to alter the 22:6 omega 3 level in rat ROS through dietary deprivation results in only minor changes in levels of 22:6 omega 3, under conditions where most other body organs show dramatic changes. However, rats raised in different levels of cyclic light show large changes in ROS 22:6 omega 3 levels. These unique features of 22:6 omega 3 in the retina, which are discussed throughout the proposal, suggest that this fatty acid is important to the normal structure and function of the retina. Furthermore, the suggestion of a defect in 22:6 omega 3 metabolism in inherited retinal degenerations makes it even more important that the metabolism of this fatty acid be studied. The long-term goal of this research project is to determine the function of 22:6 omega 3 in normal and diseased retinas. The specific aims of this five-year proposal are: 1) to study the role of 22:6 omega 3 in the inherited retinal degenerations in the miniature poodle and Abyssinian cat, 2) to determine the mechanism of conservation of 22:6 omega 3 in the rat retina during essential fatty acid deficiency, 3) to determine the role of 22:6 omega 3 in the biochemical adaptation of the rat retina to cyclic light, as related to susceptibility to acute light damage, as well as to damage by chronic exposure to cyclic light of different intensities, 4) to study the effects of chronic administration of antioxidants on the susceptibility of the retina to damage by acute constant light challenge, as well as to damage by chronic exposure to cyclic light of different intensities, and 5) to determine the site of elongation and desaturation (retinal vs. extraretinal) of 22:6 omega 3 and to study these metabolic processes. To achieve these goals, a series of in vivo and in vitro experiments are proposed in which the metabolism of 22:6 omega 3 will be studied in detail. Each step of the elongation and desaturation pathways in the formation of 22:6 omega 3 will be tested in retinas and liver homogenates of dogs and cats with inherited retinal degeneration. Rats will be raised on omega3- and/or omega6-deficient diets and injected intravitreally with lipid precursors in order to study the biochemical mechanisms of conservation of 22:6 omega 3. Similar groups of animals will be raised in bright or dim cyclic light to determine if elevated dietary PUFA levels make them more susceptible to light damage. The results of these studies will give a better understanding of the metabolism of 22:6 omega 3 in the retina and perhaps shed some light on the role of this fatty acid in retinal degenerations.