IN UTERO MURINE EMBRYO CV PHENOTYPE SCREENING

描述（改编自申请人摘要） 所有主要的结构性心血管（CV）畸形都发生在子宫内， 发生严重CV疾病的遗传“风险”存在于 出生 受过训练的胎儿超声波检查师现在可以检测出胎儿的主要结构缺陷， 在子宫内怀孕16周后的人类胎儿。 这些CV缺陷， 临床上存在于不同的年龄，取决于功能的程度， 损伤 研究人员建议开发、验证和应用 准确、高效的筛选技术来定义小鼠胚胎CV 子宫内的表型 他们还提议每年举办一次讲习班， 研究人员和学生学习基本的CV发育形态学， 综合生理学和鼠胚胎筛选技术， laboratories. 大多数用于定义胚胎CV性能的技术和应用程序， 小鸡和老鼠的胚胎已经在他们的实验室里培育出来。 这些侵入性的 体内和体外方案提供了关于正常CV的详细信息 性能（血压、血流量、腔室尺寸、血管 阻抗），正常胚胎的功能储备，以及 结构改变和功能适应之间的关系（Keller 1997，综述）。 这些技术中的大多数不能作为“筛选”技术应用， 然而，它们为确定“正常”CV提供了关键基础 结构和功能。 除了专注于胚胎CV 性能，他们现在正在定义正常的血液动力学和影响， 麻醉和实验方案对怀孕小鼠由于直接 母体血流动力学和代谢状态改变对胚胎心血管影响 功能 已经使用以下方法产生了广泛的改变的CV表型： 定向遗传和诱变技术。 影响最严重的 胚胎在子宫内死于从胚胎日（艾德）开始的血管发生失败 8.5或从艾德9.0开始CV功能失败。 其中一些改变的CV 表型已在子宫内检测到，然而，这些研究的准确性 已经变化，并且没有统一的方法来实现产妇镇静， 胚胎CV功能的技术测量，或血流动力学的解释 结果（Dyson 1995，Gui 1966，Huang 1998）。 重要的是注意到 杂合子胚胎也可能具有改变的CV表型，因此， 在初筛时检测这些胚胎 他们建议发展 胚胎CV表型筛查的标准化方法， 培训研究者在单个实验室或区域实验室进行这些筛查 中心. (End抽象）。

DESCRIPTION (Adapted from the applicant's abstract) All major structural cardiovascular (CV) malformations occur in utero and the genetic "risk" for developing serious CV disease is present at the time of birth. Trained fetal sonographers can now detect major structural defects in the human fetus after 16 weeks gestation in utero. These CV defects then present clinically at varying ages dependent on the degree of functional impairment. The investigators propose to develop, validate, and apply accurate and efficient screening technology to define murine embryo CV phenotype in utero. They also propose to provide an annual workshop for investigators and students to learn basic CV developmental morphology, integrated physiology, and murine embryo screening techniques for use in their laboratories. Most of the technology and applications to define embryonic CV performance in chick and mouse embryos has been developed in their labs. These invasive in vivo and in vitro protocols have provided detailed information on normal CV performance (blood pressure, blood flow, chamber dimensions, vascular impedance), the functional reserve of the normal embryo, and the relationship between altered structure and functional adaptation (Keller 1997, review). Most of these techniques cannot be applied as "screening" technologies, however, they provide the critical foundation for determining "normal" CV structure and function in utero. In addition to their focus on embryonic CV performance, they are now defining the normal hemodynamics and impact of anesthesia and experimental protocols on the pregnant mouse due to the direct effect of altered maternal hemodynamic and metabolic state on embryonic CV function. A wide range of altered CV phenotypes have already been produced using targeted genetic and mutagenesis techniques. The most severely affected embryos die in utero from failed vasculogenesis starting at embryo day (ED) 8.5 or failed CV function starting at ED 9.0. Some of these altered CV phenotypes have been detected in utero, however, the accuracy of these studies has varied and there has been no uniform approach to maternal sedation, technical measurement of embryo CV function, or interpretation of hemodynamic results (Dyson 1995, Gui 1966, Huang 1998). It is important to note that heterozygous embryos can also have altered CV phenotype, thus it is critical to detect these embryos during primary screening. They propose to develop standardized methods for embryonic CV phenotype screening in utero and to then train investigators to perform these screens at individual labs or regional centers. (End of Abstract.)