The Role of ARAP1 in Retinal Photoreceptor Homeostasis

ARAP1 在视网膜感光器稳态中的作用

• 批准号: 9224876
• 负责人: ALA MOSHIRI
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224876
• 关键词: ADP-Ribosylation Factors; Actins; Adult; Animal Model; Animals; Applications Grants; Area; Basic Science; Binding; Biochemistry; Biological; Biological Assay; Blindness; Blood Vessels; Cell membrane; Cell physiology; Cells; Cilia; Clinical Research; Clinical Treatment; Development; Developmental Biology; Disease Progression; Distal; Early Endosome; Electron Microscopy; Epidermal Growth Factor Receptor; Exhibits; Faculty; Funding; G-substrate; GTP-Binding Proteins; GTPase-Activating Proteins; Genes; Genetic; Goals; Golgi Apparatus; Guanosine; Homeostasis; Human; Image; In Vitro; Inherited; Knockout Mice; Ligation; Light; Membrane Protein Traffic; Mentors; Modern Medicine; Molecular; Molecular Abnormality; Molecular Biology; Morphology; Mus; Mutation; Natural History; Neurons; Optic Nerve; PH Domain; Pallor; Pathogenesis; Pathway interactions; Patients; Photons; Photoreceptors; Physiology; Pigmentation physiologic function; Presynaptic Terminals; Protein Family; Protein Sortings; Proteins; Reporter; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinitis Pigmentosa; Rhodopsin; Rod Outer Segments; Role; Scientist; Specialist; Techniques; Tertiary Protein Structure; Testing; Thinness; Training; Translational Research; Vesicle; Vision; Visual Signal Transduction Pathway; attenuation; base; cell type; design; experimental study; fascinate; genetic regulatory protein; in vitro Model; in vivo; interest; member; novel therapeutic intervention; patient population; phosphatidylinositol 3,4,5-triphosphate; photoreceptor degeneration; protein transport; retinal rods; rho; scaffold; skills; trafficking; trans-Golgi Network; vision science; visual processing

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.

项目概要 遗传性视网膜变性是年轻人失明的一个重要原因，通常是由于 视网膜感光细胞的遗传异常。目前尚无疗法可以减缓 这些疾病的进展或恢复视力。本研究旨在了解特定角色的作用 基因 Arap1，是健康光感受器功能所必需的。确定该基因的作用 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 对于我们目前没有享受到任何益处的这一重要患者群体来说，有潜在的治疗方法 来自现代医学的疗法。 该提案旨在确定如何调节光感受器的发育和功能，特别是通过 蛋白质分选、靶向和运输，重点关注最丰富、最重要和研究最深入的蛋白质 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， 我们从 U.C. 培育了 Arf GAP Arap1 中具有靶向缺失的小鼠。戴维斯淘汰赛小鼠项目 （KOMP）。我们发现 Arap1-/- 小鼠表现出类似于视网膜色素变性 (RP) 的特征 人类：视神经苍白、血管衰减、色素变化和外视网膜变薄。目标是 该提案旨在定义这种视网膜变性的自然史，确定分子和细胞 光感受器损伤的机制，并确定该小鼠作为动物的适宜性 人类隐性 RP 模型。 作为一名学术临床医生科学家和玻璃体视网膜专家，我对以下方面有临床和研究兴趣： 了解视网膜疾病的机制。具有深厚的视网膜发育生物学背景 和视网膜疾病的临床治疗，我热情地准备追求基础和转化 研究遗传性视网膜变性的发病机制和治疗。加州大学戴维斯分校提供了一个世界—— 一流的师资和设施有可能促进我在分子生物学和 生物化学、活体动物眼成像和基本感光生理学。指导和技能 通过这项拨款提案获得的资金将使我能够获得转化遗传性视网膜方面的专业知识 退化研究。