Development and function in mucociliary epithelia

摘要： 粘液纤毛上皮在正常和病理的呼吸道生物学中都发挥着关键作用，因为它提供了 抵御吸入毒剂的第一道防线。呼吸道多纤毛细胞纤毛搏动缺陷 导致遗传性和获得性呼吸道疾病的进展。 在这里，我们将研究控制MCCs发育和功能的分子机制。马达 驱动纤毛跳动的蛋白质在细胞质中组装，在以前的版本下 ，我们发现了一种新型的细胞器，其中这些电机集中在各种因素的指导下 他们的集会。这个项目的第一个目标是探索这些蛋白质之间相互作用的层次结构。 新的细胞器；第二个将探索马达被输送到纤毛中的机制，以及 第三，将使用大规模销售的蛋白质组学方法来确定对马达重要的新的蛋白质-蛋白质相互作用 装配和功能。通过快速确定几种新的蛋白质的功能参与不同的 在MCC开发过程中，本提案中的目标将为我们的理解提供关键的新深度 这些基本细胞。此外，通过将这些不同的进程链接到MCC中，这里的实验将 也为我们的理解增添了至关重要的新广度。 影响：这里提出的实验将导致对细胞生物学和遗传学的更详细的理解 微囊藻毒素和纤毛跳动。这一结果将有助于开发旨在 修复或恢复受损组织，改善呼吸道疾病患者的粘液清除。

Abstract: The mucociliary epithelium plays a key role in both normal and pathological airway biology, as it provides the first line of defense against inhaled agents. Defects in ciliary beating in multiciliated cells (MCCs) in the airway contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. The motor proteins that drive ciliary beating are assembled in the cytoplasm, and under the previous version of this award, we discovered a novel organelle in which these motors are concentrated with various factors that direct their assembly. The first Aim of this project will explore the hierarchy of interaction among proteins in these novel organelles; the second will explore the mechanisms by which motors are transported into cilia, and the third will use large-sale proteomic approaches to identify novel protein-protein interactions important for motor assembly and function. By rapidly determining the functions of several new protein involved in distinct processes in MCC development, the Aims in this proposal will provide critical new depth to our understanding of these essential cell. Moreover, by linking these the disparate processes in MCCs, the experiments here will add crucial new breadth to our understanding as well. Impact: Experiments proposed here will lead to a more detailed understanding of the cell biology and genetics of MCCs and ciliary beating. The results will aid in the development of regenerative therapies aimed at repairing or restoring damaged tissue and improving mucus clearance in patients with airway disease.