Development and function in mucociliary epithelia

摘要： 粘膜纤毛上皮在正常和病理性气道生物学中起关键作用，因为它提供了呼吸系统的功能。 是对抗吸入性毒剂的第一道防线多纤毛细胞（MCCs）的结构或功能缺陷 粘膜纤毛上皮有助于遗传性和获得性气道疾病的进展。 在这里，我们将研究控制MCCs的发育和功能的分子机制。1)我们以前的 工作证明RFX2转录在运动纤毛发生中的重要作用，在这里我们将联合收割机与 新的模型系统，体内成像，以及蛋白定位的高内容筛选，以询问Rfx2如何靶向 基因控制着肌动蛋白的组装，而肌动蛋白的组装又对纤毛的发生至关重要。2)我们以前的工作也产生了一个 更深入地了解分子异质性的复杂性，沿着运动纤毛的长度。我们将 定义了这种异质性的分子层次，并将这些机制与纤毛联系起来 心要让3)动力蛋白臂是复杂的多蛋白机器，驱动纤毛跳动和我们的蛋白质 定位屏幕表明，组装过程是划分在一个新的，MCC的具体 细胞器我们将探讨这种新的细胞器的分子和细胞生物学机制 功能通过快速确定参与不同过程的几个新基因的功能， 粘膜纤毛上皮发育，本提案的目的将为我们的研究提供关键的新深度。 了解这些重要的组织。此外，通过将粘膜纤毛的这些不同方面联系起来， 上皮生物学，这里的实验也将为我们的理解增加至关重要的新广度。 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了解。 粘膜纤毛上皮细胞的。研究结果将有助于开发旨在修复或治疗癌症的再生疗法。 修复受损组织并改善气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 the structure or function of multiciliated cells (MCCs) in the mucociliary epithelium contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. 1) Our previous work demonstrated an essential role for the RFX2 transcription in motile ciliogenesis, and here we combine a novel model system, in vivo imaging, and a high-content screen for protein localization to ask how Rfx2 target genes govern actin assembly that in turn is crucial for ciliogenesis. 2) Our previous work has also generated a deeper appreciation of the complexity of molecular heterogeneity along the length of motile cilia. We will define the molecular hierarchy by which this heterogeneity is established and we link these mechanisms to cilia beating. 3) Dynein arms are complex multi-protein machines that drive ciliary beating and our protein localization screen suggests that the assembly process is compartmentalized in a novel, MCC-specific organelle. We will explore the molecular and cell biological mechanism underlying this novel organelle's function. By rapidly determining the functions of several new genes involved in distinct processes in mucociliary epithelial development, the Aims in this proposal will provide critical new depth to our understanding of these essential tissues. Moreover, by linking these such disparate aspects of mucociliary epithelial biology, 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 mucociliary epithelia. 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.