The role of the TGFb-Par6 polarity pathway in endothelial-to-mesenchymal transition and angiogenesis

血管生成，即在原有血管的基础上形成新的血管，是循环系统发育、器官发育以及成年个体器官正常功能所必需的。血管生成也被证明是包括癌症在内的疾病的重要中介。转化生长因子-β(TGFb)在特定条件下促进血管生成，但这一作用是如何实现的还不清楚。在这里，我认为TGFb通过诱导内皮细胞到间充质细胞的转变(EnMT)来促进血管生成，EnMT是一种细胞可塑性的过程，允许最初浸泡在静态细胞层中的细胞获得迁移能力。更具体地说，我认为TGFb通过激活TGFb-Par6信号通路来诱导EnMT和血管生成，该信号通路以内皮细胞-细胞接触为靶点，允许血管生成。为了证明这些假设，我将使用生理相关条件下的血管内皮细胞三维培养，在实际生物体中重现血管生成过程的基本步骤。我将使用这些体外模型应用生化、遗传学和成像方法，首先，证明EnMT是血管生成所必需的，其次，TGFb，特别是通过激活Par6途径，诱导EnMT并促进血管生成。这项研究计划将显著提高我们对血管生成过程的认识和理解，对包括健康科学在内的基础和应用生命科学产生明显影响。该项目还将有助于生物科学学生的学术形成，并有助于培养高素质、具有国际竞争力的加拿大科学家和专业人员。

Angiogenesis, the formation of new blood vessels from pre-existing ones, is required for the development of the circulatory system, for organ development in general, and for the normal function of organs in an adult individual. Angiogenesis has also been demonstrated to be an essential mediator of disease, including cancer. Transforming growth factor-beta (TGFb) promotes angiogenesis under specific conditions, but how this effect is achieved is not well understood. Here I propose that TGFb promotes angiogenesis by inducing endothelial-to-mesenchymal transition (EnMT), a process of cellular plasticity that allows cells initially immersed in a static cell layer, to acquire the capacity to migrate. More specifically, I propose that TGFb induces EnMT and angiogenesis by activating the TGFb-Par6 signaling pathway, which targets the endothelial cell-cell contacts to permit angiogenesis. To prove these hypothesis I will use three-dimensional cultures of endothelial cells under physiologically relevant conditions, which reproduce the essential steps of the angiogenesis process in an actual organism. I will apply biochemical, genetic and imaging approaches using these in vitro models to first, demonstrate that EnMT is required for angiogenesis and second, that TGFb, specifically through the activation of the Par6 pathway, induces EnMT and promotes angiogenesis. This research program will significantly improve our knowledge and understanding of the angiogenesis process, with obvious impact on basic and applied life sciences, including health sciences. This program will also contribute to the academic formation of students in biological sciences and to the training of highly qualified, internationally competitive Canadian scientists and professionals.