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。多毛细胞(MCC)的结构或功能缺陷 黏液纤毛上皮在遗传性和获得性呼吸道疾病的进展中起着重要作用。 在这里，我们将研究控制MCCs发育和功能的分子机制。1)我们以前的 工作证明了RFX2转录在运动纤毛发生中的重要作用，在这里我们结合了一个 新的模型系统，活体成像，以及用于蛋白质定位的高含量屏幕，以询问Rfx2靶点 基因控制着肌动蛋白的组装，而肌动蛋白组装对纤毛的形成至关重要。2)我们之前的工作也产生了一个 更深刻地认识到沿活动纤毛长度的分子异质性的复杂性。我们会 定义建立这种异质性的分子体系，我们将这些机制与纤毛联系起来 打人。3)Dynein手臂是一种复杂的多蛋白质机器，可以驱动纤毛跳动和我们的蛋白质 本地化屏幕显示，组装过程被划分为一种新颖的、MCC特有的 细胞器。我们将探索这种新型细胞器背后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 粘液纤毛上皮发育，这项提案中的目标将为我们的 对这些重要组织的了解。此外，通过将粘液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理解 粘液纤毛上皮细胞。这一结果将有助于再生疗法的发展，旨在修复或 修复受损组织，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 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.