Fat-PCP and branching morphogenesis

Fat-PCP 和分支形态发生

• 批准号: BB/K001671/1
• 负责人: Philippa Francis-West
• 金额: $ 56.3万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK001671%2F1
• 关键词: Fat; PCP; branching; morphogenesis

Organs such as the kidney, lungs, salivary, prostate and mammary glands consist of epithelial and mesenchymal cells. A large surface area of epithelial cells is required for organ function. For example, the kidney and lungs require a large surface area for the removal and concentration of excretory products from the blood stream and exchange of gases during breathing respectively. For many organs these large surface areas are generated during embryonic development by the continuous branching of epithelial tubules which allow an increase in the epithelial surface area within a compact space. This is clearly illustrated by the adult lungs which have a surface area of a tennis court. A defect in branching affects the function of the organ and can also have unexpected secondary consequences. For example, defects in kidney branching are the leading cause of hypertension (high blood pressure) in adults.During development, the branching organs arise from epithelium and mesenchyme. The epithelium branches and this branching is controlled by signals from the mesenchyme. The epithelium grows and branches by combinations of signals that control proliferation and cell death. Additionally, there is cell movement and a change in cell shape. We have shown that two genes, Fat4 and Dchs1, that control the shape and orientation of cells, are essential for branching morphogenesis in the developing kidney. The proposal aims to determine how Fat4 and Dchs1 control kidney branching morphogenesis and if these proteins control branching morphogenesis in other organs. We will determine if Dchs1 and Fat4 function in the epithelium or mesenchyme and how loss or gain of Dchs1/Fat4 affects cell behaviours that contribute to branching morphogenesis. The knowledge will contribute to our understanding of cell behaviours during the growth and morphogenesis of different organs. We will determine the role of two factors that we already know are important for this process but we currently do not understand why. The knowledge will give insight into how organs develop, how developmental birth defects arise, and has relevance in stem cell biology and tissue-engineering approaches in which damaged cells/organs are replaced by newly generated cells/organs.

肾、肺、唾液、前列腺和乳腺等器官由上皮细胞和间充质细胞组成。器官功能需要较大的上皮细胞表面积。例如，肾脏和肺需要很大的表面积来分别从血液中清除和浓缩排泄物，以及在呼吸过程中交换气体。对于许多器官来说，这些大的表面积是在胚胎发育过程中通过上皮管的持续分支而产生的，这使得紧凑空间内的上皮表面积增加。成年人的肺有网球场的表面积，清楚地说明了这一点。分支缺陷会影响器官的功能，也可能产生意想不到的次要后果。例如，肾分支缺陷是成人高血压(高血压)的主要原因。在发育过程中，分支器官来自上皮和间质。上皮细胞分枝，这种分枝受间充质信号控制。上皮细胞通过控制增殖和细胞死亡的信号组合而生长和分支。此外，还有细胞运动和细胞形状的变化。我们已经证明了控制细胞形状和方向的两个基因，Fat4和DCHS1，对于发育中的肾脏的分支形态发生是必不可少的。该提案旨在确定Fat4和DCHS1如何控制肾脏分支形态发生，以及这些蛋白质是否控制其他器官的分支形态发生。我们将确定DCHS1和Fat4是否在上皮或间充质中发挥功能，以及DCHS1/Fat4的缺失或获得如何影响有助于分支形态发生的细胞行为。这些知识将有助于我们理解细胞在不同器官生长和形态发生过程中的行为。我们将确定两个因素的作用，我们已经知道这两个因素对这一进程很重要，但我们目前不明白为什么。这些知识将深入了解器官是如何发育的，发育先天缺陷是如何产生的，并在干细胞生物学和组织工程方法中具有相关性，在组织工程方法中，受损的细胞/器官被新生成的细胞/器官取代。