Regulators of polarised protein and vesicle traffic in a genetic model of vessel formation

血管形成遗传模型中极化蛋白和囊泡运输的调节剂

• 批准号: 46651-2012
• 负责人: Jacobs, Roger
• 金额: $ 2.04万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=593178
• 关键词: Regulators; polarised; protein; vesicle; traffic

Tube formation is central to the development of most organs. We examine the genetic basis of heart tube formation in the simplest genetic model organism that has a heart- Drosophila. Our objective is to determine the mechanisms of cell signaling and cell differentiation that underlie the formation of a tubular structure like a human blood vessel. As with vertebrates, the progenitors of the Drosophila heart, called cardioblasts, arise in the embryo from the most lateral of the mesoderm cells. They migrate as a group towards the midline where they meet their opposite partners and form a vessel, which matures into the heart and aorta. In both vertebrates and Drosophila, this is a major collective cell migration event, which entails coordinated movement, cell signaling and differentiation. All three processes are dependent upon detecting unidirectional (polarising) cues, which then instruct the cell to re-organise, with an asymmetrically organised internal skeleton and membrane. These events culminate in the formation of a vessel, with three molecularly different surfaces- luminal (inside), lateral (between vessel cells) and basal (outside) membrane domains. We have identified the major receptor, called Robo, that guides and polarises cardioblasts as they migrate to the midline. Robo is also required for the formation of a lumen. We know that Robo does not act alone, and we seek to identify the other signals. Employing tools unique to Drosophila, we will uncover how signals from Robo act to organise the transport of molecules and membrane to the luminal surface of the vessel. We will express proteins in heart cells only, that glow under the microscope, and allow us to follow molecular changes in the heart cells of living embryos. At the same time we can look at changes in cell behaviour, caused by mutations that affect polarity signals or molecule targeting machinery, to build a model of how signals outside the heart cell instruct the assembly of a tube. We have yet to discover the genetic factors that predispose us to congenital heart disease. This research will advance live imaging as an R&D technology, and will direct efforts to developing predictive factors in congenital heart disease.

管状结构是大多数器官发育的中心。我们研究了具有心脏的最简单的遗传模式生物--果蝇--心管形成的遗传基础。我们的目标是确定细胞信号和细胞分化的机制，这些机制是形成类似人类血管的管状结构的基础。与脊椎动物一样，果蝇心脏的祖细胞称为成心细胞，起源于胚胎最外侧的中胚层细胞。它们成群结队地向中线迁移，在那里与对方相遇，形成一条血管，成熟后进入心脏和主动脉。在脊椎动物和果蝇中，这是一个重要的集体细胞迁移事件，需要协调运动、细胞信号和分化。所有这三个过程都依赖于检测到单向(极化)信号，然后指示细胞重新组织，内部骨架和膜不对称地组织起来。这些事件最终形成一个血管，具有三个分子上不同的表面--管腔(内部)、侧面(血管细胞之间)和基膜(外部)区域。我们已经确定了主要的受体，称为Robo，当成心细胞迁移到中线时，它引导和极化成心细胞。腔的形成也需要ROBO。我们知道Robo不是单独行动的，我们寻求识别其他信号。利用果蝇特有的工具，我们将揭示来自ROBO的信号如何组织分子和膜的运输到血管的管腔表面。我们将只在心脏细胞中表达在显微镜下发光的蛋白质，并允许我们跟踪活着的胚胎心脏细胞的分子变化。与此同时，我们可以观察细胞行为的变化，这些变化是由影响极性信号或分子靶向机制的突变引起的，以建立一个模型，说明心脏细胞外的信号如何指导管子的组装。我们还没有发现使我们易患先天性心脏病的遗传因素。这项研究将推动活体成像作为一项研发技术，并将指导努力开发先天性心脏病的预测因素。