Synthetic Retinal Pigments and Binding Proteins

描述(申请人提供)：我们的长期目标是确定视黄醇在视觉转导过程中的作用，并探索视黄醇类似物在治疗因视黄醇处理不当而引起的疾病方面的潜力，例如Leber黑素症。我们的工作前提是视网膜生色团(11顺式视网膜)控制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)如果独特的红色视锥视蛋白的性质是由于没有棕榈酸酯基团锚定蛋白质的C-末端，2)如果视黄素上存在第二个视黄醇结合位点并且其完整性依赖于棕榈酸酯的存在，以及3)全反式视黄醇的形成和从外节的清除是否受视蛋白的结构特征、视蛋白/视黄醇相互作用和光感受器形态的控制。我们的第二个目标是研究视黄醇循环在视杆细胞和视锥细胞退变中的作用。研究将确定：1)在缺乏11顺式视网膜的模型中，视杆蛋白磷酸化是否减缓视蛋白活性引起的变性；2)如果不当的维生素A处理导致视锥视蛋白错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这种视锥视蛋白错位并防止视锥变性。我们预计，这些研究将为使用类维甲酸化合物治疗因维生素A加工不当而导致的致盲疾病提供合理的基础。 众所周知，维生素A是一种对视力至关重要的类维A物质。缺乏足够的维生素A可用于视觉过程，可能是由于饮食不足或未能正确处理这种化合物。我们正在研究维生素A在眼睛中的加工过程，并探索使用类维甲酸化合物治疗因维生素A加工不当而引起的疾病的药用潜力。

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.