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首页> 外文学位 >Unraveling the pathways of cardiovascular morphogenesis and congenital heart defects through classical and proteomic studies.
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Unraveling the pathways of cardiovascular morphogenesis and congenital heart defects through classical and proteomic studies.

机译：通过经典和蛋白质组学研究揭示心血管形态发生和先天性心脏缺陷的途径。

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摘要

Congenital heart defects (CHDs), the most common congenital anomaly, affects ∼1% of live births in the United States. Further, over 1 million survivors of CHDs require continual clinical care. Progress in our understanding of the genetic and molecular events that underlie cardiovascular development have been derived from the ex vivo heart and whole embryo culture models and fortuitous transgenic mice with cardiovascular phenotypes. After decades of work with these models, the pathways that govern mammalian cardiovascular morphogenesis, though slowly being unraveled, are poorly understood. Advancements in the field have been hindered by the lengthy process of creating and breeding transgenic mice and the paucity of technological approaches amenable to the ex vivo model systems. Utilization of the ex vivo model requires the a priori knowledge of the molecules of interest and the availability of appropriate reagents to study a given factor (i.e. recombinant factors, inhibitors, antibodies or tissues from transgenic mice). Embryonic structures contain small amounts of protein which limits its use in biochemical assays. Further there is a lack of readily available homogeneous cell lines derived from the embryonic heart and vasculature to perform in vitro studies. To circumvent these methodological limitations, in addition to utilizing the classical ex vivo models, a proteomic approach was employed to determine protein profiles during normal and abnormal cardiovascular development and uncover proteins previously unappreciated to have a role in the cardiovascular system. Using these approaches several proteins were found to have novel roles in cardiovascular development including nitric oxide, leptin, Wnt16, ADAM15, NOGO, laminin 1, TRPC5, ST14 and PTPN1. The data accrued through these studies highlight the importance of antioxidant, adhesion/migration, differentiation and insulin like growth factor pathways in cardiovascular development. The successful application of these proteins (MMP2, laminin 1, Wnt16, PC1/3 and SVCT) as biomarkers of congenital heart defects was confirmed in both murine and human amniotic fluid samples. Discovery of novel proteins and pathways involved in cardiovascular development will broaden our understanding of the global developmental pathways of cardiovascular morphogenesis and the pathogenic mechanisms that underlie congenital heart defects in order to diagnose, prevent and treat CHDs in the future.
机译：在美国，先天性心脏缺陷（CHD）是最常见的先天性异常，影响约1％的活产婴儿。此外，超过一百万的冠心病幸存者需要持续的临床护理。我们对离体心脏和整个胚胎培养模型以及具有心血管表型的偶然转基因小鼠的理解，对构成心血管发展的遗传和分子事件的理解取得了进步。在使用这些模型进行了数十年的研究之后，尽管缓慢地揭示了控制哺乳动物心血管形态发生的途径，但人们对其了解甚少。创建和繁殖转基因小鼠的漫长过程以及缺乏适用于离体模型系统的技术方法，已经阻碍了该领域的进展。利用离体模型需要先了解目标分子，并需要有合适的试剂来研究给定因子（即重组因子，抑制剂，来自转基因小鼠的抗体或组织）。胚胎结构包含少量蛋白质，这限制了其在生化分析中的使用。此外，缺乏从胚胎心脏和脉管系统获得的易于获得的均质细胞系来进行体外研究。为了规避这些方法学上的局限性，除了利用经典的离体模型外，还使用蛋白质组学方法来确定正常和异常心血管发育过程中的蛋白质谱，并发现以前未被认识的在心血管系统中起作用的蛋白质。使用这些方法，发现了几种蛋白质在心血管发育中具有新作用，包括一氧化氮，瘦素，Wnt16，ADAM15，NOGO，层粘连蛋白1，TRPC5，ST14和PTPN1。通过这些研究获得的数据突出了抗氧化剂，粘附/迁移，分化和胰岛素样生长因子途径在心血管发展中的重要性。这些蛋白（MMP2，层粘连蛋白1，Wnt16，PC1 / 3和SVCT）作为先天性心脏缺陷生物标志物的成功应用已在鼠和人羊水样本中得到证实。发现与心血管发展有关的新型蛋白质和途径将拓宽我们对心血管形态发生的全球发展途径以及先天性心脏缺陷基础的致病机制的认识，以便将来诊断，预防和治疗冠心病。

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  • 作者

    Nath, Anjali Katyal.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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