Synthetic Retinal Pigments and Binding Proteins

描述（由申请人提供）：我们的长期目标是确定类维甲酸在视觉转导过程中的作用，并探索视网膜类似物治疗由类维甲酸处理不当引起的疾病的潜力，例如Leber黑内障。我们的工作前提是视网膜发色团（11-cis视网膜）控制着视觉色素的生化和生理特性。我们的第一个目标是研究调节视网膜相互作用的视蛋白的结构决定因素。研究将确定：1)独特的红锥视蛋白性质是否由于缺乏锚定蛋白质c端的棕榈酸基团，2)是否存在视黄醇的二级类视黄醇结合位点，其完整性是否依赖于棕榈酸盐的存在，以及3)是否所有反式视黄醇的形成和从外部片段的清除是由视蛋白的结构特征、视蛋白/类视黄醇相互作用和光感受器形态控制的。我们的第二个目的是研究类维甲酸循环在视杆和视锥变性中的作用。研究将确定：1)在缺乏11-顺式视网膜的模型中，视蛋白磷酸化是否会减缓视蛋白活性引起的变性；2)维生素A处理不当是否会导致视蛋白错定位并最终导致视锥变性；3)如果光稳定，11-顺式视网膜的类似物可以纠正视锥蛋白错定位并防止视锥变性。我们预计这些研究将为使用类维甲酸化合物治疗由维生素a加工不当引起的致盲疾病提供合理的基础。

DESCRIPTION (provided by applicant): Our long-term goal is to define the roles of retinoids in the visual transduction process and to explore the potential of retinal analogs in treating disorders resulting from improper retinoid processing, such as in Leber's amaurosis. Our working premise is that the retinal chromophore (11-cis retinal) controls the biochemical and physiological properties of visual pigments. Our first aim is to investigate the structural determinants in opsins that modulate retinal interactions. Studies will determine: 1) if the unique red cone opsin properties are due to the absence of a palmitate group anchoring the C-terminus of the protein, 2) if a putative secondary retinoid binding site on opsins exists and if its integrity is dependent on the presence of a palmitate, and 3) if all-trans retinol formation and clearance from the outer segment are controlled by structural features of opsins, the opsin/retinoid interactions and photoreceptor morphology. Our second aim is to investigate the role of retinoid cycling in rod and cone degeneration. Studies will determine: 1) if rod opsin phosphorylation slows the degeneration arising from opsin activity in models that lack 11-cis retinal, 2) if improper vitamin A processing leads to cone opsin mislocalization and eventual cone degeneration, and 3) if light-stable, analogues of 11-cis retinal can correct this cone opsin mislocalization and prevent cone degeneration. We anticipate that these studies will form a rational basis for using retinoid-like compounds to treat the blinding diseases that result from improper vitamin A processing. The retinoid, vitamin A, is known to be essential for vision. Lack of adequate vitamin A for the visual process can arise from dietary deficiency or through a failure of processing this compound properly. We are studying the processing of vitamin A in the eye and exploring the pharmaceutical potential of using retinoid-like compounds to treat diseases resulting from improper processing of vitamin A.