Developmental Physiology of Ciliated Epithelia

描述（由申请人提供）：项目摘要：本申请的目的是确定纤毛上皮形成和功能的细胞和分子机制，使用爪蟾幼虫皮肤作为模型系统。非洲爪蟾幼虫的皮肤直接类似于哺乳动物的肺上皮，但非常容易使用分子方法和成像进行实验分析。使用该模型，所提出的实验将确定纤毛细胞如何由转录因子指定，以及它们插入上皮细胞如何由Notch信号通路调节。拟议的实验还将确定所需的分子途径，以建立在上皮平面内的纤毛细胞的极性。最后，所提出的实验将建立测定来研究纤毛功能。相关性：许多器官系统内衬有与水环境相互作用的上皮细胞。为了正常发挥功能，上皮细胞含有专门的纤毛细胞，其跳动行为建立了定向的流体流动。这种纤毛上皮细胞在呼吸道、中枢神经系统和生殖器官中发挥重要的生理功能，并且当缺陷时引起一类称为原发性纤毛功能障碍（PCD）的人类疾病。例如，肺上皮中的纤毛细胞功能障碍导致反复呼吸道感染，这是儿童的常见问题，而其他形式的纤毛功能障碍则导致脑积水、内脏逆位和不孕症。尽管纤毛上皮细胞对器官功能和人类健康的重要性，但对这些组织在胚胎发育过程中如何形成知之甚少。这些研究的结果将提供有关纤毛细胞功能障碍如何在人类疾病中出现的重要基础信息，并提供使用细胞替代治疗纤毛细胞损失的策略。

DESCRIPTION (provided by applicant): Project Summary: The goal of this application is to determine the cellular and molecular mechanisms that underlie the formation and function of ciliated epithelia, using the larval skin of Xenopus as a model system. The Xenopus larval skin is directly analogous to the pulmonary epithelium of mammals but is extremely accessible to experimental analysis using molecular approaches and imaging. Using this model, the proposed experiments will determine how ciliated cells are specified by transcription factors, and how their insertion into the epithelium is regulated by the Notch signaling pathway. The proposed experiments will also determine the molecular pathways that are required to establish the polarity of ciliated cells within the plane of the epithelium. Finally, the proposed experiments will establish assays to study cilia function. Relevance: Many organ systems are lined with an epithelia that interacts with an aqueous environment. To function properly, this epithelia contains specialized ciliated cells whose beating action sets up a directed fluid flow. Such ciliated epithelia play important physiological functions in the respiratory tract, the central nervous system and in reproductive organs, and when defective cause a class of human disease called primary ciliary dysfunction (PCD). For example, ciliated cell dysfunction in the pulmonary epithelium leads to recurrent respiratory infections, a common problem in children, while other forms of cilia dysfunction cause hydrocephaly, situs inversus, and infertility. Despite the importance of ciliated epithelia to organ function and to human health, very little is known about how such tissues form during embryonic development. Results from these studies will provide important basic information about how ciliated cell dysfunction may arise in human disease, and provide strategies for treating the loss of ciliated cells using cell replacement.