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.

项目总结