Genetic and Environmental Modifiers of Congenital Heart Disease

先天性心脏病的遗传和环境因素

基本信息

批准号：
9353842
负责人：
Karl Degenhardt
金额：
$ 8.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-17 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353842
关键词：
Adult Air Altitude Anemia Animal Model Binding Biological Models Blood Vessels CRISPR/Cas technology Cardiac Cardiovascular system Cells Child Complex Congenital Abnormality Coronary Counseling Data Defect Development Discipline Disease Embryo Endothelial Cells Environment Environmental Exposure Environmental Risk Factor Family Female Fetus Frequencies Genes Genetic Genetic Risk Genetic study Goals HIF1A gene Heart Heart Abnormalities Human Genetics Hypoxia Immunohistochemistry Individual Investigation Knock-out Life Location Lung Mediating Mediator of activation protein Molecular Mothers Mus Mutagenesis Mutant Strains Mice Mutation Neuropilin-1 Newborn Infant Oxygen Pathway interactions Pattern Penetrance Phenotype Placenta Prevention strategy Pulmonary veins Research Support Risk Role Semaphorins Signal Pathway Signal Transduction Smoking Testing Tissues Venous angiogenesis base cardiogenesis cell growth cell motility congenital heart disorder design driving force epidemiology study experimental study genetic epidemiology genetic makeup insight microCT mouse model mutant pregnant prevent receptor total anomalous pulmonary venous return

项目摘要

Project Summary Congenital heart disease (CHD) is the most common life threatening birth defect of the newborn period. CHD accounts for nearly one third of congenital defects world-wide, occurring in over one million newborns per year. Our understanding of the origins of CHD in people comes primarily from studies of Human Genetics and Epidemiology. Unfortunately, neither of these disciplines offers a complete picture. Indeed, we have come to recognize that the causes of CHD are multifactorial and depend on complex interactions between genetics and the environment. This proposal describes experiments aimed at better understanding these interactions through the use of an animal model. Sema3d mutant mice develop a type of CHD called total anomalous pulmonary venous return (TAPVR). The molecular mechanism of Sema3d in patterning the pulmonary veins has been well characterized in these mice. This mechanism suggests hypoxia and the molecular mediators of hypoxia may be potential environmental and genetic modifiers of the disease. Importantly, the Sema3d mutant mice develop TAPVR with incomplete penetrance, making them ideally suited for the study of factors that may increase or decrease the frequency of the disease, such as oxygen levels. The developing mammalian fetus receives limited oxygen from the mother through the placenta. In people, the delivery of oxygen to the placenta can be altered by altitude, anemia, or smoking. We will mimic the effect of these conditions by exposing pregnant mice to air with reduced oxygen content. We will test how this exposure influences the development of TAPVR in genetically sensitized mice. Furthermore, we will use CRISPR/Cas9 mutagenesis to target candidate genetic modifiers of Sema3d based on known interacting pathways. This approach allows a relatively high throughput means of testing molecular interactions with semaphorin signaling in the context of vascular patterning. Upon completion, these studies will provide important insights into environmental and genetic modifiers of pulmonary vein patterning resulting in TAPVR.

项目概要先天性心脏病（CHD）是新生儿期最常见的危及生命的出生缺陷。冠心病占全世界先天性缺陷的近三分之一，每年发生在超过一百万新生儿中。我们对人类冠心病起源的理解主要来自于人类遗传学和流行病学。不幸的是，这些学科都没有提供完整的情况。确实，我们已经来到了认识到冠心病的病因是多因素的，并且取决于遗传和疾病之间复杂的相互作用。环境。该提案描述了旨在更好地理解这些相互作用的实验通过使用动物模型。 Sema3d 突变小鼠患上一种称为“完全异常”的先天性心脏病肺静脉回流（TAPVR）。 Sema3d 肺静脉图案化的分子机制已经在这些小鼠身上得到了很好的表征。这种机制表明缺氧和分子介质缺氧可能是该疾病的潜在环境和遗传调节因子。重要的是，Sema3d 突变体小鼠发生 TAPVR 的外显率不完全，使它们非常适合研究可能导致 TAPVR 的因素。增加或减少疾病的发生频率，例如氧气水平。正在发育的哺乳动物胎儿通过胎盘从母亲那里获得有限的氧气。在人类中，将氧气输送到胎盘可能因海拔高度、贫血或吸烟而改变。我们将通过暴露来模拟这些条件的影响怀孕的老鼠呼吸氧气含量减少的空气。我们将测试这种暴露如何影响开发 TAPVR 在基因致敏小鼠中的应用。此外，我们将使用 CRISPR/Cas9 诱变来靶向基于已知相互作用途径的 Sema3d 候选遗传修饰剂。这种方法允许在以下情况下测试分子与信号蛋白信号传导相互作用的相对高通量的方法血管图案。完成后，这些研究将为环境和肺静脉模式的遗传修饰导致 TAPVR。