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维持 光感受器外节和视觉。在视网膜变性致盲疾病中， 光感受器外节先于光感受器神经元的死亡。一个彻底的 需要了解纤毛稳定性背后的机制，以揭示所需的分子 光感受器存活本提案的具体目标是确定翻译后的重要性 微管蛋白在维持纤毛和光感受器功能中的修饰。改变的微管蛋白修饰 是人类失明的一个已知原因我们将调查对属于 ARF样蛋白家族ARL 13 B及其在光感受器纤毛维持、微管蛋白修饰 和功能我们的研究将调查是否改变微管蛋白修饰将保护光感受器 和挽救视网膜变性疾病的各种遗传模型中的视觉反应。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， 全面解决微管蛋白修饰的需求及其在纤毛细胞中的调节 光感受器 我们提出的研究与NEI的视网膜疾病项目一致，旨在“阐明分子水平” 导致感光细胞变性的机制，包括信号转导途径， 蛋白质折叠，纤毛发生，功能区室化或运输，并翻译这些分子 为孟德尔和复杂疾病的治疗提供了基础。”拟议研究的结果 临床意义，如治疗遗传性视网膜疾病，导致失明。

PROJECT SUMMARY/ABSTRACT The long-term goal of our research is to identify mechanisms that contribute to the maintenance of photoreceptor outer segments and vision. In retinal degenerative blinding diseases, loss of ciliated photoreceptor outer segments precedes the death of photoreceptor neurons. Therefore, a thorough understanding of the mechanisms behind the stability of the cilia is needed to uncover molecules required for photoreceptor survival. The specific goal of this proposal is to identify the importance of post-translational modifications of tubulins in the maintenance of cilia and photoreceptor function. Altered tubulin modifications are a known cause of human blindness. We will investigate the need for a small GTPase that belongs to the ARF-like family of proteins, ARL13B, and its role in photoreceptor ciliary maintenance, tubulin modifications, and function. Our studies will investigate whether altering tubulin modifications will protect photoreceptors and rescue visual response in various genetic models for retinal degenerative diseases. We will use a combination of unique animal models, cell culture models, and in vitro biochemical analyses to comprehensively address the requirement for tubulin modification and their regulation in ciliated photoreceptors. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to “Elucidate the molecular mechanisms that lead to photoreceptor degeneration, including signal transduction pathways, defects in protein folding, ciliogenesis, functional compartmentalization, or trafficking, and translate these molecular footholds into therapies for Mendelian and complex diseases.” The findings from the proposed studies have clinical implications, such as therapy for inherited retinal diseases that lead to blindness.