ROLE OF ESSENTIAL FATTY ACIDS IN RETINAL DEGENERATIONS

杆段(RO)含有最高水平的多不饱和脂肪酸 人体内任何细胞膜的脂肪酸(PUFA)。许多研究表明 ROS中的主要多不饱和脂肪酸二十二碳六烯酸(22：6欧米伽3)是 对视网膜的正常功能很重要。ITS的饮食剥夺 必需前体导致视网膜电图(ERG)的改变 大鼠、灵长类动物和早产儿；灵长类动物的视力；以及 大鼠的明度辨别学习。人类、狗和猫 遗传性视网膜变性患者的血浆中22：6 omega3水平较低 而不是控制。视网膜中22：6 omega 3水平升高的大鼠 更容易受到光损害，而饮食限制为22：6 Omega 3或其前体保护免受光伤害。急性光损伤 导致ROS中22：6 omega 3的损失，表明22：6 omega过氧化 3可能是光损伤的原因之一。显然，视网膜退行性变 玻璃体内注射Fe2+是由于22：6的过氧化 Omega 3。试图通过改变大鼠ROS中22：6 omega 3的水平 缺乏饮食只会导致22：6欧米伽水平的微小变化 3、在大多数其他身体器官发生剧烈变化的情况下。 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 在ROS 22：6欧米伽3水平。22：6 omega 3的这些独特功能 整个提案都在讨论视网膜，这表明这一点 脂肪酸对视网膜的正常结构和功能很重要。 此外，22：6 omega 3代谢缺陷的建议 遗传性视网膜退行性变使得更重要的是 对这种脂肪酸的代谢进行了研究。这样做的长期目标是 研究项目是确定22：6 omega 3在正常和 视网膜病变。这个五年计划的具体目标是：1) 22：6 omega 3在遗传性视网膜变性中的作用 小型贵宾犬和阿比西尼亚猫，2)确定其发病机制 必需脂肪酸对大鼠视网膜22：6 omega 3的保护作用 缺乏，3)确定22：6 omega 3在生化中的作用 大鼠视网膜对周期性光的适应性与易感性 对急性光损伤，以及对慢性暴露于循环 不同强度的光照，4)研究慢性疲劳的影响。 给予抗氧化剂对视网膜易感性的影响 由急性持续光照挑战造成的伤害，以及由慢性光照造成的伤害 暴露在不同强度的循环光下，以及5)测定 延长和降低饱和度的部位(视网膜与视网膜外)为22：6 Omega 3，并研究这些代谢过程。为了实现这些目标，一个 提出了一系列体内和体外实验，其中 我们将详细研究22：6欧米伽3的代谢。每一步都是 22：6 omega 3 Will形成过程中的伸长和减饱和途径 在遗传性疾病的狗和猫的视网膜和肝脏匀浆中进行测试 视网膜变性。大鼠将用omega3-和/或 缺乏omega6的饮食和玻璃体内注射脂质前体 为了研究22：6欧米伽3的生物化学保存机理。 类似的动物群体将在明亮或昏暗的循环光中饲养 确定饮食中多不饱和脂肪酸水平升高是否会使他们更容易患上 轻微损伤。这些研究的结果将使我们更好地理解 22：6欧米伽3在视网膜的新陈代谢，可能会带来一些曙光 关于这种脂肪酸在视网膜退化中的作用。

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.