Epigenetic Mechanisms Underlying Maternal Diabetes Associated Cardiac Malformations

摘要 先天性心脏病是一个严重的儿童和成人健康问题。他们不是 仅代表婴儿死亡的主要非传染性原因，但成年人的数量不断增加 幸存者也遭受着严重的发病率。许多基因贡献者已经被确定为 导致先天性心脏缺陷，从染色体异常到单基因缺陷。 导致先天性心脏病的基因已经通过动物模型和 调控正常心脏形态发生的分子途径日益明确。 众所周知，环境因素会增加先天性心脏病的发生率。一个重要的 知识鸿沟存在于我们对环境因素影响机制的理解中 调节心脏发育的分子途径会增加先天性心脏病的风险。 产妇糖尿病是一种公认的、日益普遍的环境风险因素 先天性心脏病。我们最近描述了一种新的基因-环境相互作用 母体高血糖和Notch1信号增加先天性心脏病的风险 动物模型。我们的研究表明，一氧化氮表观遗传调控的变化 Notch1信号通路负责这种相互作用。我们的长期目标是 定义这种相互作用背后的分子和细胞途径，并定义一个范例，通过它 基因与环境的相互作用会导致先天性心脏缺陷。对此的总体假设是 研究表明，产妇糖尿病相关的先天性心脏病发生在产妇 高血糖诱导的活性氧通过以下途径破坏正常的心脏形态发生 表观遗传机制，并将在以下具体目标中加以解决：目标1.确定 高血糖相关氧化应激介导的细胞特异性和时间机制 NOS3基因座染色质可及性降低导致先天性心脏病。目标2.定义 一氧化氮调节表观遗传Notch1调节子表达的机制， Jarid2.目的3.确定高血糖时染色质调节基因是否发生改变 导致产妇糖尿病相关的先天性心脏病。阐明分子基础 因为糖尿病和心脏畸形之间的流行病学联系是必要的，以便 设计新的预防糖尿病相关先天性心脏病的策略，并有可能 识别处于危险中的个人。成功完成拟议的研究将带来重大的 基因-环境相互作用机制的分子理解研究进展 相互作用导致先天性心脏缺陷的发生。

Abstract Congenital heart defects constitute a significant pediatric and adult health problem. They not only represent the leading non-infectious cause of death in infants, but the growing number of adult survivors also suffer significant morbidity. Numerous genetic contributors have been identified to cause congenital heart defects ranging from chromosome abnormalities to single gene defects. Congenital heart disease-causing genes have been well-studied using animal models and the molecular pathways regulating normal cardiac morphogenesis are being increasingly defined. Environmental factors are known to increase the incidence of congenital heart defects. A significant knowledge gap exists in our understanding of the mechanisms by which environmental factors affect the molecular pathways regulating heart development to increase the risk of congenital heart disease. Maternal diabetes is a well-established and increasingly prevalent environmental risk factor for congenital heart disease. We recently described a novel gene-environment interaction between maternal hyperglycemia and Notch1 signaling that increased the risk of congenital heart defects in animal models. Our studies suggested that alterations in the epigenetic regulation of the nitric oxide and Notch1 signaling pathways were responsible for this interaction. Our long-term objective is to define the molecular and cellular pathways underlying this interaction and define a paradigm by which gene-environment interactions occur to cause congenital heart defects. The overall hypothesis of this research is that maternal diabetes-associated congenital heart disease occurs when maternal hyperglycemia-induced reactive oxygen species disrupts normal cardiac morphogenesis by epigenetic mechanisms and will be addressed in the following specific aims: Aim 1. To determine the cell-specific and temporal mechanisms by which hyperglycemia-associated oxidative stress mediates reduced chromatin accessibility at the Nos3 locus to cause congenital heart disease. Aim 2. To define the mechanism by which nitric oxide regulates the expression of the epigenetic Notch1 regulator, Jarid2. Aim 3. To determine if alterations in chromatin regulatory genes that occur with hyperglycemia contribute to maternal diabetes-associated congenital heart defects. Elucidating the molecular basis for the epidemiologic association between diabetes and cardiac malformations is required in order to devise novel preventive strategies for diabetes-associated congenital heart disease and potentially identify at risk individuals. Successful completion of the proposed studies will result in a significant advancement in our molecular understanding of the mechanisms by which gene-environment interactions contribute to congenital heart defect occurrence.