Transcriptional Regulation of Cardiac Morphogenesis

心脏形态发生的转录调控

• 批准号: 7646935
• 负责人: Daniel J. Garry
• 金额: $ 48.37万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646935
• 关键词: Address; Adult; Biochemical; Biological; Cardiac; Cardiovascular system; Cell Therapy; Cells; Childhood; Congenital Abnormality; Congenital Heart Defects; Data; Development; Embryo; Embryonic Development; Emerging Technologies; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Heart; Heart failure; In Vitro; Knockout Mice; Molecular; Molecular Profiling; Morphogenesis; Mus; Myocardial; Natural regeneration; Pathway interactions; Patients; Phenotype; Population; Process; Regulation; Research; Role; Signal Pathway; Specific qualifier value; Staging; Stem cells; Techniques; Technology; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; cardiogenesis; congenital heart disorder; embryonic stem cell; innovation; mouse model; mutant; overexpression; progenitor; public health relevance; regenerative; tissue regeneration

DESCRIPTION (provided by applicant): Congenital cardiac malformation is the most frequent birth defect and it contributes to advanced heart failure in the pediatric and adult population. An enhanced understanding of the transcriptional networks that direct cardiac progenitors during heart development will have important applications related to cell based therapies and the treatment of congenital heart disease. Furthermore, a number of parallel transcriptional pathways or networks have been proposed for the generation and regeneration of tissues such as the heart. For these reasons, we predict that the definition of the transcriptional regulatory mechanisms of cardiac progenitor cells in the developing heart will enhance our understanding of cardiogenesis, congenital heart disease and myocardial regeneration. We have recently utilized transgenic technology to isolate and characterize cardiac progenitor cells from the developing mouse heart. We have identified Etsrp71 as a potential downstream target of Nkx2-5 and generated Etsrp71 deficient embryos that are nonviable and have perturbed cardiovascular development. Our principle hypothesis is that Nkx2-5 regulated networks direct discrete stages of cardiac morphogenesis. We further predict that the Etsrp71 is a direct downstream target of Nkx2-5 and is a master regulator of the endocardial/endothelial lineages. In these proposed studies, we take an innovative approach to examine these hypotheses and employ emerging technologies to define the role of the Nkx2-5 - Etsrp71 cascade and cardiovascular development. To examine these hypotheses, we will address the following specific aims: 1) To define the Nkx2.5 transcriptional regulatory cascades in cardiac progenitor cells isolated from the developing murine heart. 2) To define the functional role of Etsrp71 during embryogenesis. 3) To determine whether Etsrp71 is a master regulator of the endocardial/endothelial lineage. These studies will enhance our understanding of the role of transcriptional networks and signaling pathways that mechanistically regulate cardiac progenitor cell (CPC) populations to acquire a cardiovascular fate during development. In addition, the results of these studies will serve as a platform for therapeutic strategies directed towards congenital heart disease and advanced heart failure. PUBLIC HEALTH RELEVANCE: Congenital heart disease is common and deadly. An increased understanding of the networks that direct cardiac progenitors and stem cells during heart development will have important therapeutic applications for the treatment of congenital heart disease. As the regulation of these progenitor cells are largely unknown, this proposal will decipher the molecular pathways that govern cardiac progenitors, which may ultimately serve as a platform to enhance the regenerative process in patients with cardiac malformations and advanced heart failure.

描述（由申请人提供）：先天性心脏畸形是最常见的出生缺陷，它会导致儿童和成人晚期心力衰竭。增强对心脏发育过程中指导心脏祖细胞的转录网络的理解，将在基于细胞的疗法和先天性心脏病的治疗方面具有重要的应用。此外，已经提出了许多平行的转录途径或网络用于心脏等组织的生成和再生。由于这些原因，我们预测，对发育中心脏中心脏祖细胞转录调控机制的定义将增强我们对心脏发生、先天性心脏病和心肌再生的理解。我们最近利用转基因技术从发育中的小鼠心脏中分离和表征心脏祖细胞。我们已将 Etsrp71 确定为 Nkx2-5 的潜在下游靶标，并生成了 Etsrp71 缺陷胚胎，这些胚胎无法存活并干扰心血管发育。我们的主要假设是 Nkx2-5 调节网络直接指导心脏形态发生的离散阶段。我们进一步预测 Etsrp71 是 Nkx2-5 的直接下游靶标，并且是心内膜/内皮谱系的主要调节因子。在这些拟议的研究中，我们采用创新方法来检验这些假设，并采用新兴技术来定义 Nkx2-5 - Etsrp71 级联和心血管发育的作用。为了检验这些假设，我们将实现以下具体目标：1）定义从发育中的小鼠心脏中分离出的心脏祖细胞中的 Nkx2.5 转录调控级联。 2) 定义Etsrp71在胚胎发生过程中的功能作用。 3) 确定Etsrp71是否是心内膜/内皮谱系的主要调节因子。这些研究将增强我们对转录网络和信号通路作用的理解，这些通路从机制上调节心脏祖细胞（CPC）群体，以在发育过程中获得心血管命运。此外，这些研究的结果将作为针对先天性心脏病和晚期心力衰竭的治疗策略的平台。公共卫生相关性：先天性心脏病很常见且致命。进一步了解心脏发育过程中指导心脏祖细胞和干细胞的网络将对先天性心脏病的治疗具有重要的治疗应用。由于这些祖细胞的调节很大程度上未知，该提案将破译控制心脏祖细胞的分子途径，这最终可能成为增强心脏畸形和晚期心力衰竭患者再生过程的平台。