Wnt and Notch Regulation of Cardiac and Vascular Smooth Muscle Gene Expression During Differentiation.

分化过程中心脏和血管平滑肌基因表达的 Wnt 和 Notch 调节。

• 批准号: 435832-2013
• 负责人: Gordon, Joseph
• 金额: $ 2.33万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629370
• 关键词: Wnt; Notch; Regulation; Cardiac; Vascular

During cardiovascular development, the heart and the great vessels that deliver blood to the body and lungs arise from at least three sources within the embryo. These include the first and second heart fields and a group of neural crest cells that migrate from the base of the skull to form the large vessels leaving the heart. Interestingly, the second heart field cells will ultimately become both heart muscle of the right ventricle and vascular smooth muscle cells of the great vessels. However, the mechanisms that determine this choice between heart and smooth muscle speciality remains unknown. Regulation of cell specialization, more generally, is regulated by secreted factors and cell-to-cell contact. The Wnt and Notch families of signaling molecules regulate cell specialization in this manner, and represent critical developmental cues that dictate organ formation in multiple biological systems. However, the role of these signaling pathways in cardiovascular development, as well as in the specialization of heart or vascular smooth muscle tissue is less understood. Interestingly, genetic inhibition of the myocyte enhancer factor 2C (MEF2C) gene in mice has uncovered a critical role for this transcription factor in cardiac second heart field and neural crest specialization. Therefore, utilizing techniques of cell and molecular biology, this research proposes to test the hypothesis that Wnt and Notch signaling pathways regulate cardiac and vascular smooth muscle specialization through modulation of MEF2C activity. Completion of this experimental objective will provide a new molecular insight into our understanding of this aspect of cardiovascular development, which could prove to be critical for future applied studies aimed at deciphering acquired and genetic defects affecting the heart.

在心血管发育过程中，心脏和向身体和肺输送血液的大血管至少来自胚胎内的三个来源。这些包括第一和第二心脏领域和一组神经嵴细胞，从颅底迁移形成离开心脏的大血管。有趣的是，第二心脏野细胞最终将成为右心室的心肌和大血管的血管平滑肌细胞。然而，决定心脏和平滑肌之间选择的机制仍然未知。更一般地，细胞特化的调节受分泌因子和细胞与细胞接触的调节。Wnt和Notch信号分子家族以这种方式调节细胞特化，并代表了决定多种生物系统中器官形成的关键发育线索。然而，这些信号通路在心血管发育中的作用，以及在心脏或血管平滑肌组织的专门化中的作用还不太清楚。有趣的是，小鼠中肌细胞增强因子2C（MEF2C）基因的遗传抑制揭示了该转录因子在心脏第二心脏领域和神经嵴特化中的关键作用。因此，本研究利用细胞和分子生物学技术，拟验证Wnt和Notch信号通路通过调节MEF2C活性调节心脏和血管平滑肌特化的假设。这个实验目标的完成将为我们理解心血管发育的这一方面提供新的分子见解，这可能对未来旨在破译影响心脏的获得性和遗传缺陷的应用研究至关重要。