Functions of the Epithelial Septate Junction

描述(由申请人提供)：上皮细胞发育和功能的一个中心问题是形成和维持特化膜域的过程。这些结构域包括顶膜和基侧膜、连接复合体和其他亚域，在组织和划分膜相关功能方面非常重要。细胞间连接，包括贴壁连接、紧密连接和分隔连接，在细胞间黏附和防止细胞旁流动方面具有明确的结构功能。此外，越来越多的证据表明，这些连接和其他特殊的膜域在调节信号通路方面发挥着重要作用。这项建议的总体目标是更好地了解特殊的膜域，包括细胞间连接和信号复合体，是如何在发育中的上皮细胞中建立和调节的。更具体地说，我们计划阐明上皮间隔连接的功能，这是果蝇上皮细胞之间形成的连接复合体的关键部分。间隔连接在结构和分子上与哺乳动物的结旁连接同源，它将Ranvier的结节与轴突的有髓部分分开。我们实验室和其他实验室的研究已经确定了几个分隔连接成分，但我们对其结构或功能的了解仍然非常有限。为了阐明这些重要的问题，我们计划：1)使用遗传和细胞方法鉴定新的间隔连接成分。2)研究Ankyrin在组织基底侧膜中的功能，Ankyrin是一种膜相关蛋白，被认为与一些间隔连接成分相互作用。3)研究间隔连接和建立和维持顶端/基底上皮极性的机制之间的功能相互作用。这些实验有望为所有发育中的组织，特别是上皮细胞提供基本重要的问题的见解。更多地了解上皮细胞建立和维持联系、调节细胞旁扩散和形成专门的膜域的机制，不仅对于理解正常的生理和发育，而且对于阐明与各种人类疾病相关的过程都是重要的。

DESCRIPTION (provided by applicant): A central problem in the development and function of epithelial cells is the process by which specialized membrane domains are formed and maintained. These domains, including the apical and basolateral membranes, the junctional complex, and other subdomains, are important in organizing and compartmentalizing membrane-related functions. Intercellular junctions, including adherens, tight, and septate junctions, have well-defined structural functions in intercellular adhesion and preventing paracellular flow. In addition, there is an increasing body of evidence that these junctions, and other specialized membrane domains, play an essential role in regulating signaling pathways. The overall goal of this proposal is to better understand how specialized membrane domains, including intercellular junctions and signaling complexes, are established and regulated in developing epithelial cells. More specifically, we plan to elucidate the functions of the epithelial septate junction, a key part of the junctional complex that forms between Drosophila epithelial cells. Septate junctions are structurally and molecularly homologous to the mammalian paranodal junction that separates the node of Ranvier from the myelinated portion of the axon. Studies in our laboratory and others have identified a handful of septate junction components, but we still have a very limited understanding of either its structure or function. To shed light on these important questions, we plan to: 1) Identify novel septate junction components using a genetic and cellular approaches. 2) Study the functions of Ankyrin, a membrane associated protein that is believed to interact with some septate junction components, in organizing the basolateral membrane. 3) Examine functional interactions between the septate junction and mechanisms that establish and maintain apical/basal epithelial polarity. These experiments are expected to provide insights into questions of fundamental importance in all developing tissues and in particular epithelia. Knowing more about the mechanisms by which epithelial cells establish and maintain contacts, regulate paracellular diffusion, and form specialized membrane domains is important not only for understanding normal physiology and development, but also for elucidating processes associated with a variety of human diseases.