PROGRESSIVE ROD-CONE DEGENERATION: SYNTHESIS AND RENEWAL

进行性视杆-视锥变性（PRCD）突变狗有一个 作为模型的进行性视网膜变性疾病 视网膜色素变性的治疗方法。 定义为视杆细胞外节（ROS）减少， 更新率 本申请中提出的研究检查了 视网膜蛋白质合成和/或转运之间的关联， 更新率、疾病和退化。 与合作者合作 也会将局部视网膜脂质和蛋白质合成联系起来 当检查不同ROS磷脂的组成时， 班 这些研究将检验扰动 在合成、运输或更新中枯萎， 细胞并导致疾病和退化。 蛋白质和脂质 研究将利用体内和体外方法。 使用 各种放射性标记的单或双标记组合 前体，将有可能检查合成，运输 或新合成蛋白质或脂质的周转。 这些研究 是基于我们维持视网膜结构完整的能力 并且在器官培养条件下具有代谢活性。 通过使用 保留疾病、象限和区域的采样方法 关系，生物化学，形态学和/或放射自显影 研究将确定疾病与 观察到的异常。 研究还建议检查视网膜的变化， 存在于PRCD基因座的退化表型。 该PRCD- 慢突变体将用于建立时间关联 更新率异常和疾病之间的关系。 由于这 突变体有一个温和的和缓慢进行性疾病，建议 实验将确定这是否是由于更新率 在较晚的年龄和/或较低程度上表达的缺陷。 另一方面，prcd突变体将用于检查是否 局部因素调节疾病，并可用于实验性地 控制疾病进展 根据我们最近的发现， 维生素E在组织中的分布与这种疾病 在PRCD视网膜地形，营养实验将检查 维生素E（边际，充足，过量）水平对 疾病的严重程度和进展。 这些研究将决定 组织维生素E水平、疾病和 退化，并确定疾病表型是否可以 在营养上被调节的（加速的，迟缓的）。

The progressive rod-cone degeneration (prcd) dog mutant has a progressive retinal degenerative disorder that serves as a model for retinitis pigmentosa in man. The disease is topographically defined and is characterized by a decreased rod outer segment (ROS) renewal rate. The studies proposed in this application examine the association between retinal protein synthesis and/or transport, renewal rate, disease and degeneration. Work with collaborators will correlate regional retinal lipid and protein synthesis as well as examining the composition of the different ROS phospholipid classes. The studies will test the hypothesis that perturbations wither in synthesis, transport or renewal compromise the visual cell and result in disease and degeneration. The protein and lipid studies will utilize both in vivo and in vitro approaches. Using single or double label combinations of various radioactively tagged precursors, it will be possible to examine the synthesis, transport or turnover of newly synthesized proteins or lipids. These studies are based on our ability to maintain the retina structurally intact and metabolically active under organ culture conditions. By using a sampling method that preserves disease, quadrant and area relationships, the biochemical, morphologic and/or autoradiographic studies will establish the causal relationship between disease and the observed abnormalities. Studies are also proposed to examine the variation in retinal degeneration phenotype that exists at the prcd locus. The prcd- slow mutant will be used to establish the temporal association between the renewal rate abnormality and disease. Since this mutant has a milder and slowly progressive disease, the proposed experiments will determine if this results from a renewal rate defect that is expressed at a later age and/ or to a lesser extent. On the other hand, the prcd mutant will be used to examine whether local factors modulate disease an can be used to experimentally manipulate disease progression. Based on our recent findings that the tissue distribution of vitamin E parallels the disease topography in the prcd retina, nutritional experiments will examine the effect of vitamin E (marginal, adequate, excess) levels on disease severity and progression. These studies will determine the association between tissue vitamin E levels, disease and degeneration and establish if the disease phenotype can be modulated (accelerated, retarded) nutritionally.