Role of delta-like ligand-4 signaling in cardiac outflow tract development

 描述(申请人提供)：先天性心脏缺陷是美国最常见的出生缺陷，每年花费国库14亿美元进行管理。了解控制正常心脏发育的信号通路为导致先天性心脏病的错乱提供了分子基础。了解导致个体患者心脏病的特定基因异常将为个性化医学铺平道路。此外，对正常心脏发育的洞察为完善旨在修复受损心脏的再生疗法提供了一个框架。心脏流出道是由第二心场产生的心脏前体细胞和神经脊细胞之间的复杂相互作用形成的。虽然Notch受体在适当的流出道发育中的作用开始被认识到，但具体配体的确切性质和来源在很大程度上是未知的。附加研究提案的中心假设是，Delta样配体-4(DLL-4)在第二心脏区域表达，并在心脏发育过程中介导Notch信号。DLL-4的表达对于心脏发育过程中心脏前体细胞的适当整合是至关重要的，它的中断会导致流出道的异常发育和咽弓尾部动脉的缺陷。使用小鼠模型的初步数据显示，在缺乏dll-4表达的情况下，第二心区细胞对发育中的心脏的贡献减少。将评估Dll-4在这些祖细胞与心脏的指定和整合中的潜在作用 在研究的目标1中。存活到妊娠中期的Dll-4突变胚胎表现出流出道排列失调和右心室双出口的表型。第二个目标将描述这些表型错位，并评估被干扰的潜在分子信号。此外，突变胚胎还表现出多种主动脉弓异常。第三个目标将是 研究这一表型，特别关注第二心区DLL-4与第二心区和神经脊细胞表达的Notch受体之间的相互作用。这项研究的成功完成将填补我们在理解Notch-Delta信号在心脏流出道发育中的重要知识空白。候选人Pi是一名早期职业生涯中的心脏外科医生兼科学家，他接受过双重培训，既是一名临床先天性心脏病外科医生，又是一名基础科学研究人员，拥有研究膜蛋白信号的博士学位。他的最终职业目标是将研究和临床培训综合起来，为临床先天性心脏病的进程提供分子基础，从而弥合板凳和床边之间的差距。这一职业发展奖将正式确定这位候选人正在进行的新研究方向的重点指导培训。为此，该提案汇集了一支强大的指导团队，提供免费技能-心脏发育生物学专业知识、对临床医生-科学家的支持、临床先天性心脏病领域的专业知识和成熟的指导工具。职业发展计划结合了教学教育、研究生存技能和对学业进步的支持。重要的是，南加州大学和PI的外科部门为卓越的研究提供了坚实的文化，拥有合格的导师，杰出的资源，并致力于促进初级临床医生-科学家的成长。

 DESCRIPTION (provided by applicant): Congenital heart defects are the most common birth defects in the United States and cost the exchequer $1.4 billion each year for management. Understanding the signaling pathways that control normal cardiac development provides a molecular basis for the derangements that cause congenital heart disease. Comprehension of the specific genetic abnormalities that result in heart disease in individual patients will pave wa for personalized medicine. Furthermore, insights into normal cardiac development provide a framework to refine regenerative therapies aimed at repairing the injured heart. The outflow tract of the heart develops from complex interactions between cardiac progenitor cells that arise from the second heart field and neural crest cells. Whereas the role of the Notch receptor in appropriate outflow tract development is beginning to be recognized, the exact nature and source of the specific ligand is largely unknown. The central hypothesis of the attached research proposal is that Delta Like Ligand-4 (DLL-4) is expressed in the second heart field and mediates Notch-signaling during cardiac development. DLL-4 expression is critically required for appropriate incorporation of cardiac progenitor cells into the developing heart and its disruption results in abnormal outflow tract development and caudal pharyngeal arch artery defects. Preliminary data using mouse models show that in the absence of DLL-4 expression, there is reduced contribution of second heart field cells to the developing heart. The potential role of DLL-4 in the specification and integration of these progenitor cells to the heart will be evaluated in Aim 1 of the study. DLL-4 mutant embryos that survive to mid-gestation show mal-alignment of the outflow tract and double outlet right ventricle phenotype. The second Aim will characterize these phenotypic derangements and evaluate the potential molecular signals that are perturbed. In addition, mutant embryos also display a variety of aortic arch abnormalities. The third Aim will study this phenotype with particular focus on the interaction between second heart field DLL-4 and Notch receptors expressed by second heart field and neural crest cells. Successful completion of this research will fill a significant knowledge void in our comprehension of Notch-Delta signaling in cardiac outflow tract development. The candidate PI is an early career cardiac surgeon-scientist, who is dual trained as a clinical congenital heart surgeon and a basic science researcher with a PhD studying membrane protein signaling. His ultimate career goal is to synthesize the research and clinical training to provide a molecular basis to clinical congenital cardiac disease processes, thereby bridge the gap between bench and the bedside. This career development award will formalize focused mentored training in a new research direction being undertaken by this candidate. Towards this end, the proposal brings together a robust mentoring team that provides complimentary skills - cardiac developmental biology expertise, support for clinician-scientist, expertise in field of clinical congenital heart disease and established mentoring tools. The career development program integrates didactic education, research survival skills and support for academic advancement. Importantly, USC and the PI's department of Surgery present a solid culture for research excellence with qualified mentors, outstanding resources and a commitment to foster the growth of junior clinician-scientists.