Importance of Small GTPases in Photoreceptor Function

小 GTP 酶在感光器功能中的重要性

• 批准号: 9893876
• 负责人: Visvanathan Ramamurthy
• 金额: $ 35.37万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893876
• 关键词: ARL2 gene; ARL3 gene; Address; Adult; Affect; Animal Model; Binding; Binding Proteins; Biochemical; Biological Assay; Blindness; Cell Culture Techniques; Cell Transplantation; Cells; Characteristics; Cilia; Clinical; Complex; Defect; Development; Disease; Embryo; Fibroblasts; Functional disorder; GTP Binding; Gene Transfer; Genes; Goals; Growth; Growth Factor; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Hydrolysis; Impairment; In Vitro; Inherited; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Length; Light; Link; Maintenance; Microtubule Polymerization; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Morphology; Mus; Mutation; Nature; Organ; Patients; Pharmacology; Phenotype; Photoreceptors; Process; Protein Family; Proteins; Regulation; Research; Retinal Degeneration; Retinal Diseases; Role; Set protein; Situs Inversus; Structure; Syndrome; System; Tamoxifen; Testing; Therapeutic; Tissue Transplantation; Transducin; Ursidae Family; Vision; conditional knockout; in vitro Assay; mouse model; mutant; novel therapeutics; phosphoric diester hydrolase; programs; protein function; protein transport; trafficking; treatment strategy

PROJECT SUMMARY/ABSTRACT The long term goals of our research are to identify mechanisms that contribute to the formation and maintenance of photoreceptor outer segments. The goal of this proposal is to explore the regulation of small GTPases that belong to the ARF-like family of proteins and their effect on early development of cilia and photoreceptor outer segment morphogenesis. Interestingly, mutations in small GTPases and their regulators are linked to blindness and syndromic diseases. Our study will also focus on the need for small GTPases in protein trafficking and will test if these GTPases are needed in adult photoreceptors. We will use a combination of unique animal models, cell culture models and in vitro biochemical analyses to comprehensively address the requirement for GTPases and their regulation in ciliated cells including photoreceptors. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to “Identify the genes involved in both inherited and retinal degenerative diseases (including RP), determine the pathophysiological mechanisms underlying these mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention”. Our proposed studies have clinical implications, such as therapy for mutations in small GTPases that lead to blindness, and which are not currently available.

项目摘要/摘要 我们研究的长期目标是确定有助于形成的机制 维持感光器外部段。该提议的目的是探索小规则 属于类似ARF的蛋白质家族的GTPases及其对纤毛和早期发展的影响 感光体外部段形态发生。有趣的是，小型GTPases及其调节器中的突变 与失明和综合症有关。我们的研究还将集中于对小GTPases的需求 蛋白质运输，并将测试成人光感受器中是否需要这些GTP酶。我们将使用一个 独特的动物模型，细胞培养模型和体外生化分析的结合到 全面满足GTPases的要求及其在纤毛细胞中的调节 感受器。 我们提出的研究与NEI的视网膜疾病计划一致，以“识别涉及的基因 在遗传和视网膜退行性疾病（包括RP）中，确定病理生理学 这些突变的基础机制，并确定治疗的新潜在治疗策略 例如基因转移，组织和细胞移植，生长因子治疗以及 药理学干预”。我们提出的研究具有临床意义，例如突变治疗 在导致失明且目前无法使用的小型GTPASE中。