Importance of Small GTPases in Photoreceptor Function

项目总结/摘要 我们研究的长期目标是确定有助于形成和 光感受器外节的维持。这项建议的目的是探讨监管小 属于ARF-样蛋白家族的GTP酶及其对纤毛早期发育的作用， 光感受器外节形态发生。有趣的是，小GTP酶及其调节因子的突变 与失明和综合症有关。我们的研究还将集中在小GTP酶的需要， 蛋白质运输，并将测试这些GTP酶是否需要在成人光感受器。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组合， 全面阐述了对GTP酶的需求及其在纤毛细胞中的调节，包括 光感受器 我们提出的研究与NEI的视网膜疾病计划一致，以“确定相关基因"。 在遗传性和视网膜变性疾病（包括RP）中，确定 这些突变的潜在机制，并确定新的潜在治疗策略， 例如基因转移、组织和细胞移植、生长因子治疗， 药物干预”。我们提出的研究具有临床意义，例如突变的治疗 在导致失明的小GTP酶中，目前还没有。

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.