Phenotyping embryonic mammalian heart function using OCT

描述(申请人提供)：心血管系统发育异常是人类最常见的先天性出生缺陷之一。小鼠已被证明是研究心血管异常发育的极好模型，在小鼠中观察到的表型范围与在人类中遇到的表型范围相媲美。在许多情况下，很明显，复杂表型的出现是因为功能受损导致了一系列掩盖原始缺陷的继发性缺陷。需要更好的工具来表征早期主要影响心血管功能的突变，这样就不会遗漏主要的功能缺陷。在这里，我们将开发使用光学相干断层扫描作为研究小鼠胚胎心血管异常的常规方法的工具。该方法比目前使用的超声方法具有更高的空间分辨率。这项研究的目的是证明OCT可以用于获得心脏功能和血流的灵敏测量，与我们在非常早期的胚胎中使用高速共聚焦显微镜获得的测量相媲美。我们的长期目标是开发交钥匙OCT系统，用于大规模筛查产生的突变小鼠的常规表型。与公共卫生相关：7.项目简介这项建议将开发新的技术和方法来研究小鼠模型中的先天性出生缺陷。每年约有35,000名儿童出生时患有先天性心血管系统缺陷，这是与出生缺陷有关的死亡的头号原因。尽管在定义正常心血管发育所需的基因方面已经取得了很大进展，但我们需要新的方法来理解这些基因的突变如何导致心脏和内皮细胞形态发生的特定变化，从而导致出生缺陷。

DESCRIPTION (provided by applicant): Abnormalities in the development of the cardiovascular system are among the most common congenital human birth defects. The mouse has proven to be an excellent model to study aberrant cardiovascular development, with the range of phenotypes observed in the mouse rivaling those encountered in humans. In many cases it is clear that complex phenotypes arise because impaired function causes an array of secondary defects that mask the original defect. Better tools are needed to characterize mutations that primarily affect cardiovascular function at early time points so primary defects in function are not missed. Here we will develop tools for using Optical Coherence Tomography as a routine method for studying cardiovascular abnormalities in mouse embryos. This method has a higher spatial resolution than currently used Ultrasound methods. The goal of this study is to show that OCT can be used to obtain sensitive measurements of heart function and blood flow, rivaling those that we have obtained in very early embryos using high-speed confocal microscopy. Our long term goal is to develop turn-key OCT systems for the routine phenotyping of mutant mice produced by large-scale screens. PUBLIC HEALTH RELEVANCE: 7. Project Narrative This proposal will develop novel technology and methods to study congenital birth defects in mouse models. Approximately 35,000 children are born each year with a congenital defect in the cardiovascular system and this is the number one cause of birth-defect related deaths. Although there has been much progress in defining genes that are required for normal cardiovascular development, we need new methods to understand how mutations in these genes cause specific alterations in cardiac and endothelial cell morphogenesis that result in birth defects.