Genetic and cellular basis of functional cilia assembly

纤毛是大多数哺乳动物细胞表面发现的特殊结构，发挥着关键的感觉功能，有时还发挥着运动功能。纤毛功能缺陷会导致一系列遗传性疾病，称为纤毛病。这些疾病可能会对人类发育(出生缺陷)或出生后健康产生破坏性影响，包括失明、肥胖和肾衰竭。数以百计的基因参与构建和维持这种高度保守的结构，这种结构是高度动态的，具有生物化学复杂性。然而，我们对为什么某些纤毛类型比其他类型的纤毛更容易受到人类疾病的影响知之甚少。为了了解不同的细胞类型如何将纤毛配置为解释环境信号的专门信号“触角”，我们设计了一系列表达最新分子标记和标记的小鼠，使我们能够精致地描述健康和疾病状态下的纤毛亚型。纤毛病是一种罕见的遗传性疾病，目前还没有有效的治疗方法。对于这些影响可及组织的疾病的一部分，如原发性睫状肌运动障碍(PCD)患者的呼吸道，我们一直在开发基因组编辑策略，以确定我们能否有效地固定正确的细胞类型，以及这是否具有良好的治疗耐受性。我们希望更好地了解纤毛疾病的发病机制，以便制定有效的诊断和治疗策略，使患者及其家人受益。

Cilia are specialized structures found on the surface of most mammalian cells, playing key sensory and sometimes movement functions. Defects in cilia function result in a broad range of genetic diseases termed ciliopathies. These can have devastating effects on human development (birth defects) or postnatal health, including blindness, obesity and kidney failure. Hundreds of genes are involved in building and maintaining this highly conserved structure, which is highly dynamic and biochemically complex. However, we know very little about why some cilia types are more affected in human disease than others. In order to understand how different cell types have configured cilia as specialized signaling ‘antennae’ to interpret environmental signals, we have engineered a series of mice expressing the latest molecular tags and markers to allow us to exquisitely profile cilia subtypes, in both healthy and diseased states. Ciliopathies are rare genetic diseases, for which there are no effective treatments. For a subset of these diseases affecting accessible tissues, like the airways of primary ciliary dyskinesia (PCD) patients, we have been developing genome editing strategies to determine can we fix the right cells types efficiently and whether this is treatment well-tolerated. We hope to better understand the disease mechanisms underlying ciliopathies in order to develop effective diagnostic as well as therapeutic strategies to benefit patients and their families.