权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Emergence of functional polarity in a tubular epithelium: a mechanistic study

管状上皮功能极性的出现：机制研究

基本信息

批准号：
BB/N001281/1
负责人：
Barry Denholm
金额：
$ 44.92万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN001281%2F1
关键词：
Emergence functional polarity tubular epithelium

项目摘要

Many of the tissues in our bodies are built up around complex arrays of cellular tubes, which permit the entry, exit, and transport of life-sustaining molecules such as oxygen, glucose, and water. But these tubes do more than simple convey materials to and fro - they also carry out vital roles in modifying the material passing through them. Functional differences along epithelial tubes are a prevalent feature in the organs in our bodies; the origin of these differences is underpinned by regional cell differentiation. The microscopic unit that makes up our kidney - the nephron - is a good example. One end is specialised to filter the blood, producing the primary urine. The tubular system that receives this urine has distinct segments with cells differing in their transport properties and permeabilities to water, salts and other compounds. It is these sequences of activity along the proximal-to-distal (P-D) axis of the nephron - a property we define as 'functional polarity' - that allows the kidney to produce and concentrate urine. The mechanisms that orchestrate the emergence of functional polarity are not well understood for most organs. This proposal focuses on how functional polarity is established along the P-D axis of the simple cellular tubule in the fruit fly (Drosophila) renal system.The insect renal system or Malpighian tubule (MpT) is the major organ for excretion, removal of wastes and toxins, and it controls the body's salt and water budget. MpTs are simple cellular tubes that contain a handful of different cell types, and a small number of cells overall (~120 in Drosophila). Yet this simplicity belies several distinct and vitally important activities. These include (but are not limited to) secretion of urine, reabsorption from the urine (to retrieve valuable materials, and to regulate fluid and salt) and control of the body's calcium levels. These different activities are carried out in spatially restricted segments of the tubule. Their order of execution underscores organ function (e.g. it is clearly important to produce urine before modification can take place). The simplicity of the MpT, its experimental tractability, and an ability to measure function, makes it an ideal subject to tackle the fundamental question outlined here.We will investigate three alternative mechanisms that might specify the P-D axis: (a) Overlapping chemical signals act to establish a 'dartboard-like pattern' of wedges and concentric rings of differential gene expression superimposed onto a flat sheet of cells. When the tubule telescopes-out from the sheet as a 3-D structure, the bullseye, mid ring- and outer ring-cells develop alternative identities based on these concentric rings of gene activity. (b) Asymmetric chemical signal(s) are issued from the base (P) and tip (D) of the developing tubule. Cells experience differing concentrations of the signal(s) depending on their position along the P-D axis, and use this to guide their differentiation. (c) Cell proliferation in the tubule is tightly controlled and occurs sequentially in distinct phases. This birth order acts to controls differentiation: with early-, mid- and late-born cells developing into alternative cell-types. We will also investigate an identified set of 'control genes', known as transcription factors (TFs), which have segment specific activities. We suggest these TFs are activated by the developmental mechanism(s) outlined above, and these in turn, activate genes encoding the channels and transport proteins that ultimately execute the activities of secretion, reabsorption and calcium handling. Using a variety of genetic methods to manipulate and mark different sets of cells, we will identify the networks and connections between genes that map out the emergence of functional polarity along the P-D axis of MpTs. We anticipate our work will lead to a better understanding of the development and function of the tubular organs of our own bodies.

我们身体中的许多组织都是围绕着复杂的细胞管阵列建立的，这些细胞管允许氧气，葡萄糖和水等维持生命的分子的进出和运输。但这些管道不仅仅是简单地来回输送材料-它们还在改变通过它们的材料方面发挥着重要作用。沿着上皮管的功能差异是我们体内器官的普遍特征;这些差异的起源是由区域细胞分化所支持的。构成肾脏的微观单位--肾单位--就是一个很好的例子。一端专门用于过滤血液，产生初级尿液。接收这种尿液的肾小管系统具有不同的节段，其中细胞的运输特性和对水、盐和其他化合物的渗透性不同。正是这些沿着肾单位的近端到远端（P-D）轴的活动序列-我们定义为“功能极性”的属性-允许肾脏产生和浓缩尿液。对于大多数器官来说，协调功能极性出现的机制还没有得到很好的理解。果蝇肾系统（Malpighian tubule，MpT）是排泄、清除废物和毒素的主要器官，控制着体内的盐和水收支，其功能极性是沿着P-D轴建立的。MpT是简单的细胞管，包含少数不同的细胞类型，总体上有少量细胞（果蝇中约120个）。然而，这种简单性掩盖了几个不同的和至关重要的活动。这些包括（但不限于）尿液的分泌，尿液的重吸收（以回收有价值的物质，并调节液体和盐）和控制身体的钙水平。这些不同的活动是在空间受限的小管段进行的。它们的执行顺序强调了器官的功能（例如，在进行修改之前产生尿液显然很重要）。MpT的简单性、实验上的易处理性和测量功能的能力使其成为解决这里概述的基本问题的理想对象。我们将研究可能指定P-D轴的三种替代机制：（a）重叠的化学信号作用于建立一个“飞镖板样模式”，即差异基因表达的楔形和同心环叠加在一张平板细胞上。当小管从薄片中以三维结构伸缩出来时，靶心、中环和外环细胞基于这些基因活性的同心环发展出不同的身份。(b)不对称化学信号从发育小管的基部（P）和尖端（D）发出。细胞经历不同浓度的信号，这取决于它们沿P-D轴的沿着位置，并使用这一点来指导它们的分化。(c)小管中的细胞增殖受到严格控制，并在不同的阶段依次发生。这种出生顺序控制着分化：早期、中期和晚期出生的细胞发育成不同的细胞类型。我们还将研究一组确定的“控制基因”，称为转录因子（TF），具有片段特异性活性。我们认为这些TF被上述发育机制激活，这些反过来又激活编码通道和转运蛋白的基因，最终执行分泌，重吸收和钙处理的活动。利用各种遗传学方法来操纵和标记不同的细胞组，我们将确定基因之间的网络和连接，这些基因沿着MpTs的P-D轴沿着绘制出功能极性的出现。我们预计我们的工作将导致更好地了解我们自己身体的管状器官的发展和功能。