BIOLOGICAL FUNCTIONS OF ESSENTIAL FATTY ACIDS

这项拟议的研究的目的是研究分子 视网膜中必需脂肪酸缺乏的基础，这是 它包含了一个有价值的、唯一可访问的模型 哺乳动物的神经系统。目前的知识表明，长期 源于必需的omega3脂肪酸的链状多不饱和脂肪酸 酸可能在视网膜和大脑发育中发挥重要作用。 对大鼠和恒河猴的研究表明， 饮食变化引起的眼部电反应功能 含二十二碳六烯酸的膜磷脂的含量 (22：6 omega3，缩写DHA)。这些研究引发了讨论。 关于长链多不饱和脂肪酸是否 如DHA应添加到婴儿配方奶粉中。此外，还有 对omega3/omega6必需脂肪比率的日益关注 西式饮食中的酸。视网膜视杆的视觉过程是 由视觉蛋白视紫红质构象变化触发 嵌入杆外段(ROS)的膜内。我们会 检验视网膜视杆细胞盘膜性质的假设 脂肪和蛋白质成分通过其调节视觉功能 对视紫红质MI-MII构象转变的影响 视觉激发中的触发事件。视网膜ROS盘膜 非常丰富的磷脂，含有高度的 多不饱和脂肪酸，包括DHA和花生四烯酸 (20：4 omega6)。我们认为视紫红质与 多不饱和膜脂调节心肌梗死和心肌梗死的自由能 MII构象状态，从而改变了关键的扩增步骤 涉及信号转导的G蛋白(转导蛋白)和cGMP 磷酸二酯酶。这些反过来影响cGMP门控血浆的关闭。 膜上钠离子通道，并随后产生一种视觉 神经冲动。多不饱和膜脂含量的变化 由于饮食或疾病改变了光解的MI-MII平衡 视紫红质，并影响视网膜的电反应。闪光灯 将应用和进一步发展光解方法来监测 多不饱和脂类对心肌梗死-心肌缺血再灌注损伤的影响 膜重组体中的视紫红质。我们将特别强调 在研究这两个多不饱和酰链的作用时 膜的组成以及膜的极性头基组成 磷脂。多不饱和膜磷脂的影响 在视觉光反应的后期放大阶段 研究包括G蛋白的结合和激活 (转导蛋白)到光解视紫红质，随后激活cGMP 磷酸二酯酶。最后，核磁共振(核磁共振) 光谱学将产生物理化学的补充知识。 多不饱和磷脂的性质及其与磷脂的相互作用 膜中的视觉蛋白。对……作用的全面了解 视觉过程中的多不饱和磷脂将在 与必需omega3膳食调查结果的关系 动物和人类的脂肪酸缺乏症。

The objective of the proposed research is to investigate the molecular basis for essential fatty acid deficiency in the retina, which is part of the brain and comprises a valuable and uniquely accessible model for the mammalian nervous system. Current knowledge indicates that long chain polyunsaturated fatty acids derived from essential omega3 fatty acids may play an important role in retinal and brain development. Studies of both rats and rhesus monkeys indicate a marked alteration of the electrical response functions of the eye due to dietary alteration of the content of membrane phospholipids containing docosahexaenoic acid (22:6omega3, abbreviated DHA). These studies have stimulated discussion regarding the question of whether long-chain polyunsaturated fatty acids such as DHA should be added to infant formulas. Moreover there is increased concern regarding the ratios of omega3 / omega6 essential fatty acids in the western diet. The process of vision in retinal rods is triggered by a conformational change of the visual protein rhodopsin embedded within the membranes of the rod outer segment (ROS). We will test the hypothesis that the properties of the retinal rod disk membrane lipid and protein constituents govern visual function through their influences on the MI-MII conformational transition of rhodopsin, the triggering event in visual excitation. The retinal ROS disk membranes are extraordinarily abundant in phospholipids, containing highly polyunsaturated fatty acidS, including DHA and arachidonic acid (20:4omega6). We propose that interactions of rhodopsin with polyunsaturated membrane lipids modulate the free energies of the MI and MII conformational states, thus altering key amplification steps involving the signal transducing G protein (transducin) and cGMP phosphodiesterase. These in turn affect closure of the cGMP-gated plasma membrane sodium channels, and subsequently the generation of a visual nerve impulse. Changes in the content of polyunsaturated membrane lipids due to diet or disease shifts the MI-MII equilibrium of photolyzed rhodopsin, and influence the electrical response of the retina. Flash photolysis methods will be applied and further developed to monitor the influences of polyunsaturated lipids on the MI-MII transition of rhodopsin in membrane recombinants. Particular emphasis will be placed upon investigating the role of both the polyunsaturated acyl chain composition as well as the polar head group composition of the membrane phospholipids. The influences of polyunsaturated membrane phospholipids on later amplification stages of the visual photoresponse will be investigated including the binding and activation of the G protein (transducin) to photolyzed rhodopsin, and subsequent activation of cGMP phosphodiesterase. Finally, nuclear magnetic resonance (NMR) spectroscopy will yield complementary knowledge of the physicochemical properties of polyunsaturated phospholipids and their interactions with visual proteins in membranes. A comprehensive picture of the role of polyunsaturated phospholipids in the visual process will be provided in relation to the results of dietary investigations of essential omega3 fatty acid deficiency in animals and humans.