Developmental Physiology of Ciliated Epithelia

描述(申请人提供)：项目摘要：本申请的目标是以非洲爪哇幼虫皮肤为模型系统，确定纤毛上皮形成和功能的细胞和分子机制。非洲爪哇幼虫的皮肤直接类似于哺乳动物的肺上皮，但非常容易用分子方法和成像进行实验分析。使用这个模型，拟议的实验将确定纤毛细胞是如何由转录因子指定的，以及它们插入上皮细胞是如何由Notch信号通路调节的。拟议中的实验还将确定在上皮平面内确定纤毛细胞极性所需的分子通路。最后，拟议的实验将建立研究纤毛功能的方法。相关性：许多器官系统都有一层与水环境相互作用的上皮细胞。为了正常发挥功能，这种上皮细胞含有特殊的纤毛细胞，它们的搏动作用建立了定向的液体流动。这种纤毛上皮在呼吸道、中枢神经系统和生殖器官中发挥着重要的生理功能，当缺陷时会导致一类人类疾病，称为原发性睫状体功能障碍(PCD)。例如，肺上皮中的纤毛细胞功能障碍会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会导致脑积水、倒位和不孕。尽管纤毛上皮对器官功能和人类健康很重要，但人们对这种组织在胚胎发育过程中是如何形成的知之甚少。这些研究的结果将为纤毛细胞功能障碍在人类疾病中如何发生提供重要的基本信息，并为使用细胞替代治疗纤毛细胞丢失提供策略。

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.