Identifying regulatory networks that govern primary cilia remodeling and neural signaling

项目摘要/摘要 初级纤毛是存在于大多数脊椎动物细胞上的几个微米的感觉器。他们皈依了 将周围的线索转化为对细胞功能至关重要的细胞内信号。纤毛浓缩键 Sonic Hedgehog途径的调节器和一系列多功能分子，包括G 蛋白偶联受体和第二信使。尽管纤毛在胚胎时期的重要性是显而易见的 许多组织和器官的发育和动态平衡，控制着 纤毛本身尚不清楚。原发纤毛功能障碍可导致多种发育综合征 神经缺陷和认知障碍。尽管大多数神经元都有初级纤毛，但它仍然是 未知这种细胞器如何调节神经元的形态和连通性。我的长期目标是 研究小组的任务是：i)发现支配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地自我重塑的基本原理，以及iii)揭示了 大脑中的神经元纤毛。在缺乏这种知识的情况下，确定纤毛的潜在易驯化修饰物 监管仍将是困难的，尤其是在大脑方面。我们采用跨学科的方法，使用不偏不倚 筛选策略、小鼠模型、尖端显微镜以及细胞和分子生物学。这个 在过去五年中取得的进展对于确定新的分子基础是至关重要的。 神经元的初级纤毛动力学和纤毛组成。我们将继续在这些第一步的基础上提供帮助 针对被扰乱的纤毛通路的先进治疗策略。

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.