Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms

项目摘要 大多数非综合征性结构性出生缺陷的原因仍然未知，因为其原因复杂， 遗传和环境因素（GxE）相互作用导致疾病。了解GxE如何收敛到 改变胚胎发育对于制定预防战略以减少风险至关重要。最近的工作 Zohn实验室建立了一种新的小鼠模型来研究GxE相互作用的机制， 先天性心脏病（CHD）。对这种小鼠模型的广泛初步研究使我们制定了我们的 中心假设：GxE会聚以改变心脏祖细胞中的基因表达，从而改变细胞命运，以及 关键基因中的不同遗传变异对GxE相互作用具有不同的影响。 我们提出了两个特定的目标，使用我们的GxE小鼠模型来阐明GxE如何相互作用， 冠心病我们的实验设计涉及改变母体饮食中的维生素A含量（环境 因子）在携带Hectd 1（遗传因子）突变的小鼠中，Hectd 1是在Zohn中发现的一种新型泛素连接酶。 实验室我们发现，虽然Hectd 1杂合突变和轻度维生素A缺乏症都不会导致 在冠心病中，两者的结合导致冠心病。从机制上讲，我们证明Hectd 1是必需的， 维生素A/视黄酸信号传导，但HECTD 1如何调节信号传导仍然未知。 该项目的目的是1）确定GxE如何收敛以导致我们模型中的CHD，2） 阐明HECTD 1如何利用截短的HECTD 1小鼠的等位基因系列调节视黄酸信号传导 模拟人类CHD相关突变的细胞系。有趣的是，我们的初步研究表明， HECTD 1的突变以不同的方式破坏视黄酸信号传导。 这些目标的成功完成将：1）提供一个更深层次的机制如何GXE相互作用的理解 通过阐明在我们的GxE模型中哪些关键发育过程被破坏来引起CHD; 3） 揭示HECTD 1如何调节RA信号传导; 4）通过建模将我们的动物研究与人类疾病联系起来 小鼠模型中的患者突变，并确定这些突变如何与母体 维生素A摄入量这些研究将揭示GxE相互作用如何改变发育的机制， 心脏和精确定位预防出生缺陷的关键目标。

PROJECT SUMMARY The causes of most non-syndromic structural birth defects remain unknown due to their complex causes where genetic and environmental factors (GxE) interact to cause disease. Understanding how GxE converges to alter embryonic development is critical for devising preventive strategies to reduce risks. Recent work by the Zohn laboratory established a new mouse model to study the mechanisms underlying GxE interactions and congenital heart defects (CHDs). Extensive preliminary studies with this mouse model led us to formulate our central hypotheses: GxE converges to alter gene expression in cardiac progenitor cells to alter cell fate, and different genetic variants in critical genes can have divergent effects on GxE interactions. We propose two Specific Aims that use our GxE mouse models to illuminate how GxE interacts to cause CHDs. Our experimental design involves altering the vitamin A content of the maternal diet (Environmental factor) in mice carrying a mutation in Hectd1 (Genetic factor), a novel ubiquitin ligase discovered in the Zohn laboratory. We show that while neither heterozygous mutation of Hectd1 nor mild vitamin A deficiency results in CHDs, the combination of the two causes CHDs. Mechanistically we demonstrate that Hectd1 is required for vitamin A/retinoic acid signaling, yet how HECTD1 regulates signaling remains unknown. The aims of this project are 1) to determine how GxE converges to cause CHDs in our model and 2) to elucidate how HECTD1 regulates retinoic acid signaling utilizing an allelic series of truncated HECTD1 mouse lines that model human CHD-associated mutations. Interestingly, our preliminary studies indicate that distinct mutations in HECTD1 disrupt retinoic acid signaling differently. Successful completion of these aims will: 1) provide a deeper mechanistic understanding of how GXE interacts to cause CHDs by elucidating which critical developmental processes are disrupted in our GxE model; 3) reveal how HECTD1 regulates RA signaling; and 4) link our animal studies to human disorders by modeling patient mutations in mouse models and determining how these mutations differentially interact with maternal vitamin A intake. These studies will reveal the mechanisms of how GxE interaction alters the development of the heart and pinpoint critical targets for preventing birth defects.