PHYSIOLOGY AND PATHOPHYSIOLOGY OF PHOTORECEPTORS

视网膜变性是导致老年人失明的主要原因 人口以及数以万计的美国年轻人 患有遗传性视网膜变性，如视网膜炎 色素变性(RP)。光感受器退化是最终的共同途径 导致视力丧失的许多侮辱眼睛，包括许多 视紫红质或其他光转导蛋白的突变 卡斯卡德。视杆细胞特异性基因突变引起的视网膜退行性变 基因，同样重要的是理解为什么正常锥体 光感受器也会死亡，将患者从夜盲带到附近 完全失明。我们建议在两个新的特征上进行实验 常染色体显性遗传性视网膜色素变性的动物模型 携带突变视紫红质的猪。这笔赠款将回答三个重要的问题 问题：(1)P347L和P347S视紫红质突变是如何改变的 正常的光转导和杆状信号？(2)如何 单细胞光响应的电生理记录比较 的间接方法派生的相同响应。 视网膜电图(ERG)？该项目将记录ERG的能力 作为探测光感受器功能的工具。棒材的大量损失 这些动物和RP患者的光感受器以某种方式杀死 视锥感光器也是如此。如果锥体函数可以挽救，则一个 人类视觉行为的很大一部分将保持不变。(3) 视锥细胞感光细胞生理的病理变化是什么？ 与视紫红质突变引起的视网膜变性有关 猪? 在过去的十年里，人们对 光传导的生物化学和分子生物学，但很少是 了解光感受器的病理生理学。我们将调查 采用吸电极技术的单电池光电流 检查整个视网膜过程中发生的变化 退化和失明。的几个生物物理参数 杆和锥体将在以下期间分3到5个阶段进行测量 所有的杆子和一半的圆锥体都不见了。我们还将研究 光感受器对闪烁光的反应被预测为 细胞健康的灵敏指示器。统计分析将确定 主要影响和次要影响。我们将建立一个定量的生理学 退行性视网膜的光感受器功能数据库 在同一疾病阶段对视网膜进行ERG检查。这 数据库将是判断治疗干预的有用依据。

Retinal degeneration is a major cause of blindness in our elderly population as well as the tens of thousands of younger Americans afflicted with inherited retinal degenerations such as retinitis pigmentosa (RP). Photoreceptor degeneration is a final common pathway resulting in loss of vision for many insults to the eye, including many mutations of rhodopsin or other proteins of the phototransduction cascade. In retinal degenerations caused by mutations in rod-specific genes, it is equally important to comprehend why the normal cone photoreceptors also die bringing patients from night blindness to near total blindness. We propose experiments on two newly characterized animal models of autosomal dominant retinitis pigmentosa, the transgenic pig carrying mutant rhodopsin. This grant will answer three important questions: (1) How do the P347L and P347S rhodopsin mutations alter normal phototransduction and rod signaling? (2) How do electrophysiological recordings of single cell photoresponses compare to those same responses derived by indirect methods with the electroretinogram (ERG)? This project will document the ERG's capacity as a tool used to probe photoreceptor function. Massive loss of rod photoreceptors in these animals and in patients with RP somehow kills the cone photoreceptors as well. If cone function could be rescued, a substantial portion of human visual behavior would remain intact. (3) What are the pathologic changes in the physiology of cone photoreceptors associated with retinal degeneration due to rhodopsin mutations in the pig? The past decade has seen tremendous advances in the understanding of the biochemistry and molecular biology of phototransduction, yet little is known about photoreceptors pathophysiology. We will investigate the single cell photocurrents with the suction electrode technique to examine the changes that take place throughout the course of the retinal degeneration and loss of vision. Several biophysical parameters of the rods and cones will be measured at 3 to 5 stages over a period in which all the rods and half the cones are lost. We will also examine the photoreceptor responses to flickering light which is predicted to be a sensitive indicator of cell health. Statistical analyses will determine major and minor effects. We will establish a quantitative physiological database for photoreceptor function in a degenerating retina coordinated with ERG evaluations of the retina at the same stages of disease. This data base will be useful in judging therapeutic intervention.