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

TGFb-Par6极性通路在内皮间质转化和血管生成中的作用

• 批准号: 386442-2010
• 负责人: ViloriaPetit, Alicia
• 金额: $ 2.33万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528880
• 关键词: role; TGFb; Par6; polarity; pathway

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.

血管生成，即从先前存在的血管形成新血管，是循环系统发育、一般器官发育以及成年个体器官正常功能所必需的。血管生成也已被证明是疾病（包括癌症）的重要介质。转化生长因子β（TGF β）在特定条件下促进血管生成，但这种作用是如何实现的还不清楚。在这里，我提出，TGF β促进血管生成诱导内皮细胞间质转化（EnMT），细胞可塑性的过程，使细胞最初沉浸在一个静态的细胞层，获得迁移的能力。更具体地说，我建议TGF β诱导EnMT和血管生成通过激活TGF β-Par 6信号通路，其靶向内皮细胞-细胞接触，以允许血管生成。为了证明这些假设，我将在生理相关条件下使用内皮细胞的三维培养物，其再现了实际生物体中血管生成过程的基本步骤。我将应用生物化学，遗传学和成像方法，使用这些体外模型，首先，证明EnMT是血管生成所需的，其次，TGF β，特别是通过激活Par 6通路，诱导EnMT和促进血管生成。这项研究计划将大大提高我们对血管生成过程的认识和理解，对基础和应用生命科学，包括健康科学产生明显的影响。该计划还将有助于生物科学学生的学术形成，并培养高素质，具有国际竞争力的加拿大科学家和专业人士。