Dissection of the genetic and molecular underpinnings of heart valve development

剖析心脏瓣膜发育的遗传和分子基础

• 批准号: 262392696
• 负责人: Professor Dr. Steffen Just
• 金额: --
• 依托单位: Klinik für Innere Medizin II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262392696?language=en
• 关键词: Dissection; genetic; molecular; underpinnings; heart

Defective development of heart valves accounts for in 20-30% of congenital malformations. However, in most cases, the underlying genetic and molecular causes have not been identified yet. There is increasing evidence that the regulatory mechanisms governing normal heart valve development also contribute to human valve pathology. We recently have shown that a novel Protein Kinase D2 (PKD2) dependent signalling pathway is involved in the regulation of cardiac valve development by controlling HDA5-Notch1 signaling specifically in endocardial cells of the atrioventricular canal (AVC). In the proposed research we now aim (1) to characterize the role of the PKD2-HDAC5-NOTCH1 signaling cascade on the initiation and progression of endothelial-to-mesenchymal transition (EMT) of endothelial cells in vitro and in vivo. Furthermore, we aim (2) to dissect the genetic and molecular pathology of the novel zebrafish heart valve mutant tailback. Finally, we aim (3) to identify the heart-specific tailback-interactome using yeast two hybrid technology and to in vivo characterize these tailback interacting proteins by overexpression and knock-down studies in zebrafish. In summary, the proposed research will ultimately help to further dissect the genetic etiology and pathophysiology of human heart valve diseases, which is essential for the development of more specific treatment strategies.

心脏瓣膜发育不良占先天性畸形的20-30%。然而，在大多数情况下，潜在的遗传和分子原因尚未确定。越来越多的证据表明，正常心脏瓣膜发育的调节机制也有助于人类瓣膜病理学。我们最近已经表明，一种新的蛋白激酶D2（PKD 2）依赖性信号通路参与心脏瓣膜发育的调节，通过控制HDA 5-Notch 1信号特异性地在房室管（AVC）的内皮细胞。在拟议的研究中，我们现在的目标是（1）在体外和体内表征PKD 2-HDAC 5-NOTCH 1信号级联对内皮细胞内皮间质转化（EMT）的启动和进展的作用。此外，我们的目标（2）解剖的遗传和分子病理学的新斑马鱼心脏瓣膜突变体tailback。最后，我们的目标是（3）使用酵母双杂交技术鉴定心脏特异性尾相互作用蛋白，并通过在斑马鱼中的过表达和敲低研究来体内表征这些尾相互作用蛋白。总之，拟议的研究将最终有助于进一步剖析人类心脏瓣膜疾病的遗传病因学和病理生理学，这对于制定更具体的治疗策略至关重要。