Epigenetic Mechanisms Underlying Maternal Diabetes Associated Cardiac Malformations

摘要 先天性心脏缺陷构成了一个重要的儿童和成人健康问题。他们不 仅代表婴儿死亡的主要非传染性原因，但越来越多的成年人 幸存者也有严重的发病率。已经确定了许多遗传因素， 导致先天性心脏缺陷，从染色体异常到单基因缺陷。 先天性心脏病的致病基因已经通过动物模型得到了很好的研究， 调节正常心脏形态发生的分子途径正被越来越多地确定。 已知环境因素会增加先天性心脏病的发病率。显著 知识差距存在于我们对环境因素影响的机制的理解中 调节心脏发育的分子途径增加先天性心脏病的风险。 母亲糖尿病是一个公认的和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Notch 1信号增加了先天性心脏缺陷的风险， 动物模型我们的研究表明，一氧化氮的表观遗传调节的改变， Notch 1信号通路负责这种相互作用。我们长远的目标是 定义这种相互作用的分子和细胞途径，并定义一种范式， 基因与环境的相互作用会导致先天性心脏缺陷。这个问题的总体假设 研究表明，当母亲患有糖尿病相关的先天性心脏病时， 高血糖诱导的活性氧通过以下途径破坏正常心脏形态发生 表观遗传机制，并将在以下具体目标解决：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 Nos 3位点的染色质可及性降低，导致先天性心脏病。目标二。以限定 一氧化氮调节表观遗传Notch 1调节因子表达的机制， Jarid 2.目标3：为了确定高血糖症是否会导致染色质调节基因的改变， 导致母体糖尿病相关的先天性心脏缺陷。阐明分子基础 糖尿病和心脏畸形之间的流行病学联系是必需的， 为糖尿病相关的先天性心脏病制定新的预防策略， 识别有风险的个人。若能顺利完成拟议的研究， 我们对基因-环境相互作用机制的分子理解的进展 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.