The Role of ARAP1 in Retinal Photoreceptor Homeostasis

项目摘要 遗传性视网膜变性是年轻人失明的重要原因， 视网膜感光细胞的遗传异常。目前没有治疗方法可以减缓 这些疾病的发展或恢复视力。这项研究旨在了解一种特定的 Arap 1基因，这是健康的感光功能所必需的。确定该基因在 光感受器扩展了对视网膜生理学的基本理解，也开辟了新的途径， 对于我们的患者人群中的这一重要群体来说，这是一种潜在的治疗方法， 现代医学的疗法。 该建议旨在确定感光细胞的发育和功能是如何调节的，特别是通过 蛋白质分选、靶向和运输，重点关注最丰富、最重要和研究最多的 外节中的蛋白质，视紫红质（RHO）。为了研究RHO运输到连接纤毛的作用， 我们产生了来自U.C.的Arf GAP Arap 1靶向缺失的小鼠。戴维斯敲除小鼠项目 （KOMP）。我们发现，Arap 1-/-小鼠表现出类似视网膜色素变性（RP）的特征， 人类：视神经苍白、血管衰减、色素改变和外部视网膜变薄。的目标 这项建议是为了确定这种视网膜变性的自然史，确定分子和细胞 感光细胞损伤的潜在机制，并确定这种小鼠作为动物的适用性 人类隐性RP模型。 作为一名学术临床科学家和玻璃体视网膜专家，我对以下方面的临床和研究感兴趣： 了解视网膜疾病的机制。在视网膜发育生物学方面有很强的背景 和视网膜疾病的临床治疗，我热情地准备追求基础和翻译 研究遗传性视网膜变性的发病机制和治疗方法。加州大学戴维斯分校提供了一个世界- 一流的教师和设施，有潜力促进我在分子生物学领域的培训， 生物化学、活体动物眼部成像和基础感光生理学。指导和技能 获得这项赠款建议将使我能够获得翻译遗传视网膜的专业知识， 退化研究

PROJECT SUMMARY Hereditary retinal degenerations are an important cause of blindness in young people, and frequently are due to genetic abnormalities in photoreceptor cells of the retina. No current therapies exist to slow down progression of these diseases or to restore vision. This research seeks to understand the role of a specific gene, Arap1, which is required for healthy photoreceptor functioning. Determining the role of this gene in photoreceptors expands the basic understanding of retinal physiology, and also opens new avenues of potential therapy for this important group of our patient population who currently do not enjoy any beneficial therapies from modern medicine. This proposal seeks to determine how photoreceptor development and function is regulated, in particular by protein sorting, targeting and trafficking, with a focus on the most abundant, most important and best-studied protein in the outer segment, Rhodopsin (RHO). To study the role of RHO trafficking to the connecting cilium, we generated mice with a targeted deletion in the Arf GAP Arap1 from the U.C. Davis Knockout Mouse Project (KOMP). We have found that Arap1-/- mice exhibit features reminiscent of Retinitis Pigmentosa (RP) in humans: optic nerve pallor, vascular attenuation, pigmentary changes, and outer retinal thinning. The goal of this proposal is to define the natural history of this retinal degeneration, determine the molecular and cellular mechanisms underlying the photoreceptor damage, and to determine the suitability of this mouse as an animal model of recessive RP in humans. As an academic clinician-scientist and vitreoretinal specialist, I have both clinical and research interests in understanding the mechanisms of retinal diseases. With a strong background in retinal developmental biology and clinical treatment of retinal diseases, I am enthusiastically prepared to pursue basic and translational research to study the pathogenesis and treatment of hereditary retinal degenerations. UC Davis offers a world- class faculty and facilities that has the potential to facilitate my training in areas of molecular biology and biochemistry, live animal ocular imaging, and fundamental photoreceptor physiology. The mentoring and skills acquired with this grant proposal will enable me to attain expertise in translational hereditary retinal degeneration research.