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

项目总结 大多数非综合征性结构性出生缺陷的原因仍不清楚，因为它们的原因复杂， 遗传和环境因素(GxE)相互作用导致疾病。了解GxE如何融合到 改变胚胎发育对于制定预防策略以降低风险至关重要。最近的工作由 Zohn实验室建立了一个新的小鼠模型来研究GxE相互作用和 先天性心脏病(CHDS)。对这种小鼠模型的广泛初步研究使我们形成了我们的 中心假设：GxE汇聚改变心脏祖细胞的基因表达，从而改变细胞命运 关键基因中不同的遗传变异会对GxE相互作用产生不同的影响。 我们提出了两个特定的目标，使用我们的GxE小鼠模型来说明GxE如何相互作用来导致 CHDS。我们的实验设计包括改变母亲饮食中的维生素A含量(环境 Hectd1(遗传因素)突变的小鼠，这是一种在Zohn基因中发现的新泛素连接酶 实验室。我们表明，虽然Hectd1杂合突变和轻度维生素A缺乏症都不会导致 在CHDS中，两者的结合会导致CHD。从机理上讲，我们证明了Hectd1是 维生素A/维甲酸信号转导，但HECTD1如何调节信号转导尚不清楚。 该项目的目标是：1)确定GxE如何融合在我们的模型中导致CHD；2) 利用截短的HECTD1小鼠等位基因序列阐明HECTD1如何调节维甲酸信号 模拟人类冠心病相关突变的品系。有趣的是，我们的初步研究表明， HECTD1的突变以不同的方式干扰维甲酸信号转导。 成功完成这些目标将：1)提供对GxE如何相互作用的更深层次的机械性理解 通过阐明在我们的GxE模型中哪些关键的发育过程被破坏来导致CHDS；3) 揭示HECTD1如何调节RA信号；以及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 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.