Identifying regulatory networks that govern primary cilia remodeling and neural signaling

项目概要/摘要 初级纤毛是存在于大多数脊椎动物细胞上的几微米的感觉细胞器。他们转换 将周围的线索转化为细胞内信号，这些信号对细胞功能至关重要。纤毛集中的关键 Sonic Hedgehog途径的调节剂和广泛的多功能分子类别，包括G 蛋白偶联受体和第二信使。尽管纤毛在胚胎发育过程中的重要性显而易见， 许多组织和器官的发育和体内平衡，控制调节的机制， 纤毛本身仍不清楚。原发性纤毛功能障碍引起多种发育综合征， 神经缺陷和认知障碍。尽管大多数神经元都有初级纤毛， 目前尚不清楚这种细胞器如何调节神经元的形态和连接。我的长期目标 研究小组的目标是i）发现控制纤毛生物发生的新机制和过程，ii）定义 纤毛如何以及为什么动态重塑本身的基本原理，以及iii）揭示未充分探索的作用， 大脑中的神经纤毛在缺乏这些知识的情况下，识别潜在的易处理的纤毛修饰剂 调节仍然很困难，特别是在大脑中。我们采用跨学科的方法， 筛选策略、小鼠模型、尖端显微镜以及细胞和分子生物学。的 在过去五年中取得的进展在确定新的分子基础方面至关重要， 初级纤毛动力学和神经元中的纤毛组成。我们将在这些初步步骤的基础上继续努力， 推进针对纤毛通路紊乱的治疗策略。

Project Summary/Abstract Primary cilia are sensory organelles of a few microns that are present on most vertebrate cells. They convert surrounding cues into intracellular signals that are critical for cellular functions. The cilium concentrates key regulators of the Sonic Hedgehog pathway and a wide range of versatile classes of molecules, including G protein-coupled receptors and second messengers. Despite the clear importance of cilia during embryonic development and the homeostasis of many tissues and organs, the mechanisms that govern the regulation of cilia themselves remain unclear. Primary cilia dysfunction causes a variety of developmental syndromes with neurological defects and cognitive impairment. Even though most neurons have a primary cilium, it is still unknown how this organelle modulates neuron morphology and connectivity. The long-term goals of my research group are to i) discover novel mechanisms and processes that govern cilium biogenesis, ii) define the fundamentals of how and why the cilium dynamically remodels itself, and iii) uncover the underexplored roles of neuronal cilia in the brain. In the absence of such knowledge, identifying potential tractable modifiers of cilia regulation will remain difficult, particularly in the brain. We employ an interdisciplinary approach using unbiased screening strategies, mouse models, cutting-edge microscopy, and cell and molecular biology. The advancements made over the last five years have been critical in identifying novel molecular foundations of primary cilia dynamics and ciliary composition in neurons. We will keep building on these first steps to help advance therapeutic strategies targeting perturbed ciliary pathways.