Cellular and Genetic Determinants of Great Vessel Morphogenesis

大血管形态发生的细胞和遗传决定因素

• 批准号: 8602524
• 负责人: CAROLINE E BURNS
• 金额: $ 42.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602524
• 关键词: Angioblast; Animal Model; Arteries; Binding Proteins; Birth; Blood; Blood Vessels; Branchial arch structure; Cardiac; Cardiovascular system; Cells; Collection; Complex; Coronary artery; Cre-LoxP; Custom; Data; Defect; Development; Dissection; Dyes; Embryo; Embryonic Development; Endothelium; Environmental Risk Factor; First Pharyngeal Arch; Fluorescence; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Programming; Genetic Screening; Goals; Heart; Human; Hypoplastic Left Heart Syndrome; Image; Imagery; Investigation; Learning; Life; Location; Maps; Mediating; Mesoderm; Molecular; Morphogenesis; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Population; Reagent; Reporter; Research; Role; Signal Transduction; Source; Testing; Therapeutic; Time; Transcript; Zebrafish; base; chemical genetics; follow-up; human disease; improved; loss of function; malformation; novel; progenitor; programs; research study

Malformations involving the large arteries that exit the heart (e.g. "the great vessels") are common causes of congenital cardiovascular defects (CCDs). In most circumstances, the genetic basis for these abnormalities has not been identified. During embryogenesis, the great vessels arise from six pairs of bilaterally symmetrical arteries embedded within the pharyngeal arches that undergo extensive remodeling to produce the complex pattern present at birth. Although the remodeling aspects have been extensively studied, the developmental origin of pharyngeal arch arteries (PAAs) and the genetic programs regulating their specification remain elusive. As severe great vessel defects are incompatible with life and milder deficiencies cause CCDs, our long-term goal is to elucidate the cellular source of PAA endothelium and identify genetic pathways mediating PAA establishment to potentially identify novel human disease genes. The zebrafish model organism allows for unparalleled real-time visualization and genetic dissection of PAA development. Through examination of a novel Tg(nkx2.5::ZsYellow) reporter line, we discovered ZsYellow fluorescence in PAA endothelium. This observation was surprising as nkx2.5 transcripts are not detected in this population. Based on these data, we postulate that PAA endothelium derives from an earlier nkx2.5+ cellular source in which ZsYellow fluorescence has persisted. Although completely unexplored, this hypothesis is supported by traditional nkx2.5 cre/loxP lineage tracing in mice. Thus, it is likely that nkx2.5 plays a conserved, yet heretofore unrecognized, role in great vessel establishment that warrants further investigation. Our preliminary data also demonstrate that nkx2.5 and a requisite TGF¿ pathway component, Latent TGF¿ Binding Protein 3 (LTBP3), are required for PAA development, but dispensable for induction of the remaining vasculature. Based on compelling preliminary data that include genetic lineage tracing, loss-of-function, and gene expression studies, I propose to test the hypothesis that LTBP3-mediated TGF¿ signaling from the second heart field (SHF) promotes endothelial differentiation of nkx2.5-expressing PAA progenitors. Having developed new reagents for illuminating nkx2.5+ progenitors and their derivatives, our lab has the unique opportunity to directly test this hypothesis. As PAA defects cause CCDs or embryonic lethality, the proposed studies are significant for improved therapeutic approaches.

畸形涉及退出心脏的大动脉（伟大的血管”） 先天性心血管缺陷的常见原因（CCD）。 这些异常的遗传基础尚未确定。 大容器来自六对嵌入的双向对称动脉 经过大量重塑以产生复合物的成对拱门 出生时出现的模式。 伴侣弓动脉（PAAS）和遗传程序的发育起源 规范仍然难以捉摸。 与生活和温和缺陷的不相容性导致CCD，我们的长期目标是 阐明PAA内皮的细胞来源并识别遗传途径 介导PAA建立，以潜在地识别新的新型人类疾病基因。 斑马鱼模型有机体可实现无与伦比的实时可视化和 PAA发育的遗传解剖。 TG（NKX2.5 :: Zsyellow）记者线，我们在PAA中发现Zsyellow荧光 内皮。 这个人口。 早期的NKX2.5+细胞来源，其中Zsyellow荧光持续存在。 尽管完全没有探索，但该假设得到了传统的NKX2.5的支持。 Cre/loxp谱系在小鼠中追踪。 迄今未得到应有的作用，在伟大的船只机构中的作用进一步 调查我们的初步数据也证明了NKX2.5 tgf¿途径组件，潜在TGF¿结合蛋白3（LTBP3）是必需的 PAA的开发，但可以根据剩余的Vasculatore进行分配 引人入胜的初步数据，包括遗传谱系追踪，功能丧失和 基因表达研究，我建议检验LTBP3介导的TGF®的假设。 来自第二心脏场（SHF）的信号促进 NKX2.5表达PAA祖先。 NKX2.5+祖细胞及其衍生物，我们的实验室具有直接的独特机会 测试此截图。 研究对于改进的治疗方法很重要。