Molecular principles of mammalian cilia diversity

纤毛是在大多数哺乳动物细胞类型的表面上发现的基于微管的小结构，并且发挥重要的感觉和有时运动功能。纤毛是胚胎发育所必需的，出生后，我们如何看，听，闻，呼吸，排泄和繁殖。超过200个影响纤毛结构和/或功能的基因的突变导致超过40种被称为纤毛病的综合征状况的不断增长的列表。然而，患者基因型和相关表型之间的不一致性越来越大，纤毛病变作为一个组具有可变的严重程度和表达特征。这部分是因为哺乳动物纤毛库的惊人的结构和功能多样性，与组装和最终分子结构的动力学的潜在差异仍然在很大程度上未被探索。我们的理解中的这些差距影响了基因诊断，临床管理和纤毛病治疗的发展。我们识别新的疾病基因，建立新的疾病模型，并揭示基本的疾病机制。我们在小鼠体内设计了强大的体内生物传感器和基于邻近的蛋白质组学报告，开始分析哺乳动物纤毛库的差异。我们产生了新的基因组编辑报告分子，以真实的时间跟踪靶向原代细胞和控制体内编辑结果的差异能力，从而使我们能够推动“基因组手术”的努力，以纠正罕见疾病，如纤毛病变。我们与国内外的患者咨询小组合作，起草政策文件，并在整个大流行期间担任国际纤毛和中心体社区的中心。在这里，我们将利用我们开发的专业知识和资源来测试令人兴奋的新假设，解决纤毛多样性如何在基因水平上固定下来，而且还在空间和时间水平上自适应地整合，以允许细胞通过这些纤毛执行专门的功能。我们将探索不同哺乳动物纤毛类型对功能障碍的潜在易感性的基础，并制定策略，以逆转这些细胞和组织水平的表型与基因组疗法。

Cilia are small, microtubule-based structures found on the surface of most mammalian cell types and that play important sensory and sometimes motile functions. Cilia are required for embryonic development and postnatally, for how we see, hear, smell, breathe, excrete and reproduce. Mutations in over 200 genes that affect cilia structure and/or function result in a growing list of over 40 syndromic conditions termed the ciliopathies. However, there is a growing discordance between patient genotype and associated phenotypes, with variable severity and expressivity characteristic of the ciliopathies as a group. This is in part because of the staggering structural and functional diversity of the mammalian cilia repertoire, with the underlying differences in dynamics of assembly and final molecular architecture still largely unexplored. These gaps in our understanding impact genetic diagnosis, clinical management and the development of therapeutics for the ciliopathies.We identify novel disease genes, build new disease models and uncover fundamental disease mechanisms. We engineer powerful in vivo biosensors and proximity-based proteomics reporters in mice to begin to profile differences in the mammalian cilia repertoire. We generate novel genome editing reporters to track in real time the differential ability to target primary cells and control editing outcomes in vivo, thereby enabling us to drive efforts towards 'genome surgery' so as to correct rare diseases like ciliopathies. We work with patient advisory groups nationally and internationally, drafted policy documents and acted as a hub for the international cilia and centrosome community throughout the pandemic.Here, we will harness the expertise and resources that we have developed to test exciting new hypotheses addressing how cilia diversity is hardwired at a genetic level, but also adaptively integrated at a spatial and temporal level to allow the cell to execute specialized functions via these cilia. We will explore the basis of the underlying susceptibility of different mammalian cilia types to dysfunction, and develop strategies to reverse these cellular and tissue level phenotypes with genome therapies.