Genetic and Environmental Modifiers of Congenital Heart Disease

先天性心脏病的遗传和环境因素

• 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
• 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

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.

项目摘要 先天性心脏病（CHD）是新生儿时期最常见的生命出生缺陷。冠心 在全球范围内，近三分之一的先天性缺陷占每年超过100万的新生儿。 我们对冠心病的起源的理解主要来自对人类遗传学和 流行病学。不幸的是，这些学科都没有提供完整的图片。确实，我们来了 认识到冠心病的原因是多因素的，并且取决于遗传学与 环境。该建议描述了旨在更好地理解这些互动的实验 通过使用动物模型。 SEMA3D突变小鼠发展了一种称为总异常的CHD 肺静脉回流（TAPVR）。 SEMA3D的分子机制在造成肺静脉的构图 这些小鼠的特征已经很好。这种机制表明缺氧和分子介质的 缺氧可能是该疾病的潜在环境和遗传修饰剂。重要的是，sema3d突变体 小鼠出现不完整的外渗的TAPVR，使其非常适合研究可能的因素 增加或减少疾病的频率，例如氧气水平。发育中的哺乳动物胎儿 通过胎盘从母亲那里获得有限的氧气。在人中，将氧气输送到胎盘 可以通过高度，贫血或吸烟来改变。我们将通过暴露来模仿这些条件的影响 怀孕的小鼠氧气含量减少。我们将测试这种暴露如何影响发展 TAPVR在遗传敏化的小鼠中。此外，我们将使用CRISPR/CAS9诱变来靶向 SEMA3D的候选遗传修饰符基于已知的相互作用途径。这种方法允许 在相对较高的吞吐量手段与词汇素信号传导测试分子相互作用的背景下 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剂导致TAPVR。