Role of epicardial-derived Slit signalling in heart development

心外膜源性 Slit 信号在心脏发育中的作用

• 批准号: BB/W015277/1
• 负责人: Joaquim Nunes Vieira
• 金额: $ 76.09万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015277%2F1
• 关键词: Role; epicardial; derived; Slit; signalling

The heart is the first organ to form in the embryo and plays an essential role by continuously pumping blood and nutrients to tissues and organs during the human lifespan. Over the last years, intensive research conducted in numerous laboratories around the world has improved our understanding of the cells and molecules required for the complex process of heart formation. Nonetheless, cardiac disabilities remain the most common organ malformations present at birth leading to congenital heart disease (CHD), and in the majority of cases, we still do not understand how they arise in the human embryo, making prevention and treatment challenging. Likewise, while cardiovascular disease is the most common cause of death worldwide, the development of new therapies to treat the diseased heart is lagging, compared with other fields of medicine (e.g. cancer). One major bottleneck hampering progress is the lack of sufficient knowledge on the biological processes affected in heart disease. A greater understanding of the intricate mechanisms regulating normal heart formation and function would therefore have a critical impact on how we prevent or treat CHD in newborns and heart disease in adult patients. My research group investigates such mechanisms and this work focus on the role of a group of cells forming the external surface of the heart, the epicardium. During pregnancy, cells from the epicardium (epicardial-derived cells or EPDCs) become activated in a process called epithelial-to-mesenchymal transition (EMT) and contribute to heart blood vessels (coronaries) and muscle (myocardium) growth and function. We recently, identified two secreted proteins called Slit2 and Slit3 produced by EPDCs, and found that mouse embryos lacking Slit2 and Slit3 in the epicardium exhibited heart malformations similar to what have been described in newborns suffering from CHD. Our observations suggest a previously unsuspected role for Slit2 and Slit3 produced by the epicardium in normal heart development. In the project, we will expand our initial findings by detailing multiple aspects of heart development from coronary and lymphatic vessel expansion to cardiac muscle growth and valve formation in these and other, more specific mouse models. Then, we will investigate how cells from the epicardium regulate EMT activation to support normal development by employing cutting-edge approaches such as next-generation sequencing that enables the analysis of all the genes active in one specific cell type at a given time. This will lead to the identification of the network of cells and molecules stimulated by Slit2 and Slit3. Such cells and molecules will be tested pharmacologically in cell culture systems via the use of drugs or antibodies to inhibit or stimulate their biological activity.

心脏是胚胎中形成的第一个器官，在人类一生中不断向组织和器官输送血液和营养物质，发挥着至关重要的作用。在过去的几年里，在世界各地的许多实验室进行的密集研究提高了我们对心脏形成复杂过程所需的细胞和分子的理解。尽管如此，心脏残疾仍然是出生时最常见的导致先天性心脏病(CHD)的器官畸形，在大多数情况下，我们仍然不知道它们是如何在人类胚胎中产生的，这使得预防和治疗具有挑战性。同样，尽管心血管疾病是全球最常见的死亡原因，但与其他医学领域(如癌症)相比，治疗心脏病的新疗法的开发滞后。阻碍进展的一个主要瓶颈是对心脏病影响的生物过程缺乏足够的知识。因此，更好地了解调节正常心脏形成和功能的复杂机制将对我们如何预防或治疗新生儿冠心病和成年患者心脏病具有关键影响。我的研究小组研究了这种机制，这项工作的重点是形成心脏外表面的一组细胞的作用，即心外膜。在怀孕期间，来自心外膜的细胞(心外膜衍生细胞或EPDCs)在称为上皮向间充质转化(EMT)的过程中被激活，并有助于心脏血管(冠脉)和肌肉(心肌)的生长和功能。最近，我们鉴定了由EPDCs产生的两种分泌蛋白Slit2和SLIT3，并发现在心外膜中缺乏Slit2和SLIT3的小鼠胚胎表现出类似于先心病新生儿的心脏畸形。我们的观察表明，心外膜产生的SLIT2和SLIT3在正常心脏发育过程中发挥了先前未被怀疑的作用。在该项目中，我们将通过详细描述心脏发育的多个方面来扩展我们的初步发现，从冠状动脉和淋巴管扩张到这些和其他更具体的小鼠模型中的心肌生长和瓣膜形成。然后，我们将研究来自心外膜的细胞如何通过使用尖端方法来调节EMT的激活以支持正常发育，例如下一代测序，它使得能够分析在给定时间在一种特定细胞类型中活跃的所有基因。这将导致对Slit2和SLIT3刺激的细胞和分子网络的识别。这些细胞和分子将通过使用药物或抗体在细胞培养系统中进行药理学测试，以抑制或刺激它们的生物活性。