IN UTERO MURINE EMBRYO CV PHENOTYPE SCREENING

描述(改编自申请人的摘要) 所有主要的结构性心血管(CV)畸形都发生在子宫和 发生严重心血管疾病的遗传“风险”存在于 出生。训练有素的胎儿超声师现在可以检测出心脏的主要结构缺陷 人类胎儿在宫内妊娠16周后。那么这些简历缺陷 根据功能性程度的不同年龄出现在临床上 减损。调查人员建议开发、验证和应用 准确高效的筛选技术确定小鼠胚胎CV 子宫内表型。他们还建议为以下人员提供年度研讨会 研究人员和学生学习基本的简历发育形态， 综合生理学和小鼠胚胎筛选技术在其 实验室。 定义胚胎CV性能的大多数技术和应用程序 鸡和老鼠的胚胎已经在他们的实验室里开发出来了。这些入侵 体内和体外方案提供了关于正常简历的详细信息 性能(血压、血流量、腔室大小、血管 阻抗)、正常胚胎的功能储备以及两者之间的关系 在结构改变和功能适应之间(Keller 1997，回顾)。 这些技术中的大多数都不能作为“筛选”技术来应用， 然而，它们为确定“正常”简历提供了关键基础 子宫内的结构和功能。除了专注于胚胎简历之外 性能，他们现在正在定义正常的血流动力学和影响 麻醉和实验方案对妊娠小鼠的直接影响 母体血流动力学和代谢状态改变对胚胎变异的影响 功能。 已经产生了广泛的改变的CV表型 有针对性的遗传和突变技术。受影响最严重的 胚胎从胚胎日(ED)开始就因血管生成失败而死于子宫内 8.5或从ED 9.0开始的CV功能失败。其中一些修改后的简历 在子宫中检测到了表型，然而，这些研究的准确性 有多种不同的方法，而且还没有统一的母体镇静方法， 胚胎心血管功能的技术测量，或血流动力学的解释 结果(Dyson 1995，Gui 1966，Huang 1998)。值得注意的是， 杂合子胚胎也可以改变CV表型，因此这是至关重要的 在初步筛选过程中检测这些胚胎。他们建议开发 宫内及以后胚胎CV表型筛选的标准化方法 培训调查人员在各个实验室或地区进行这些筛查 中锋。(摘要结束。)

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.)