RETINAL PATHOPHYSIOLOGY

视网膜色素变性（RP）是视力丧失的主要原因， 美国的该补助金的主要重点是在生理 儿童和年轻人的杆损失机制。 两个关键 在过去的赠款期间的发展影响了方向， 这次更新。一个是鉴定基因突变， 占视网膜色素变性的家庭约50%， 显性形式和5 - 10%的患者为隐性形式。是 有理由相信，其他基因的突变很快就会被发现。 在其他患者中发现了这种疾病。由于这些 已经在影响视杆细胞感光器的基因中发现了突变 功能，并提供了新的分类依据，我们的研究杆 光感受器功能将集中在已知突变的患者身上。 第二个发展激励这一建议是成功的建模 的激活阶段的转导杆兰姆和普格。我们有 表明兰姆和皮尤模型符合人道杆的前缘 ERG a波因此，a波提供了一个直接的，定量的测量， 人视杆细胞活性。由于Lamb和Pugh模型基于 在转导的活化阶段的生化步骤上，它提供了 将杆生理学缺陷与特定缺陷联系起来的强大框架 RP患者的基因突变。拟议的研究将评估 光转导级联中的放大，失活 机制，感光细胞更新机制和区域变化， 光感受器功能 许多RP患者为显性形式，大多数患者为X连锁 RP的形式，具有低于正常水平的ω-3脂肪酸（FA）， 二十二碳六烯酸（DHA），在红细胞（RBC）脂质中。可能性不大 omega-3脂肪酸异常会导致视网膜色素变性，但是， DHA在感光膜功能中重要作用，DHA缺乏 可能会影响进展的速度。我们一直在跟踪一个大型的 一组患者，每年一次，具有敏感的ERG， 视杆细胞和视锥细胞功能的心理物理测量。我们会得到血液 用于DNA和脂质分析的样本，并与表型和 进展速度。 供体眼的形态学研究表明RP中神经节细胞丢失。 近年来，一种新的基于扫描激光的成像技术 检眼镜已经发展到测量神经的厚度 纤维层这种方法被称为视网膜激光椭圆偏振法， 利用神经纤维层是双折射结构的事实 使穿过它的光偏振，并且该层的厚度是 由反射的偏振光的量来指示。神经测量 RP患者的纤维层厚度将与视觉检查结果进行比较。 田间损失、损失持续时间、表型和基因型。这些研究将 提供了第一个体内定量测量的程度， RP患者的跨神经节细胞变性。

Retinitis pigmentosa (RP) represents a major cause of visual loss in the United States. The primary focus of this grant has been on physiological mechanisms of rod loss in children and young adults. Two critical developments over the past grant period have influenced the direction of this renewal. One is the identification of gene mutations that at present account for retinitis pigmentosa in approximately 50% of families with dominant forms and from 5 to 10% of patients with recessive forms. It is reasonable to expect that mutations in additional genes will soon be identified to account for the disease in additional patients. Since these mutations have been identified in genes that affect rod photoreceptor function and provide a new basis for classification, our research on rod photoreceptor function will focus on patients with known mutations. The second development motivating this proposal is the successful modeling of the activation phase of transduction in rods by Lamb and Pugh. We have shown that the Lamb and Pugh model fits the leading edge of the humane rod ERG a-wave. Thus the a-wave provides a direct, quantitative measure of human rod photoreceptor activity. Since the Lamb and Pugh model is based on biochemical steps in the activation stage of transduction, it provides a powerful framework for relating defects in rod physiology to specific gene mutations in patients with RP. Proposed studies will evaluate amplification within the phototransduction cascade, deactivation mechanisms, photoreceptor renewal mechanisms, and regional variations in photoreceptor function. Many patients with dominant forms of RP, and most patients with X-linked forms of RP, have lower than normal levels of an omega-3 fatty acid (FA), docosahexaenoic acid (DHA), in red blood cell (RBC) lipids. It is unlikely that omega-3 FA abnormalities cause retinitis pigmentosa but, given the important role of DHA in photoreceptor membrane function, DHA deficiency may influence the rate of progression. We have been following a large group of patients at yearly intervals with sensitive ERG and psychophysical measures of rod and cone function. We will obtain blood samples for both DNA and lipid analyses and relate both to phenotype and rate of progression. Morphological studies in donor eyes have shown ganglion cell loss in RP. Recently, a new imaging technology based on the scanning laser ophthalmoscope has been developed to measure the thickness of the nerve fiber layer. This methodology, known as retinal laser ellipsometry, utilizes the fact that the nerve fiber layer is a birefringent structure that polarizes light passing through it and the thickness of the layer is indexed by the amount of reflected polarized light. Measures of nerve fiber layer thickness in patients with RP will be compared with visual field loss, duration of loss, phenotype and genotype. These studies will provide the first in vivo, quantitative measures of the degree of transneuronal ganglion cell degeneration in patients with RP.