The Role of RERE in Congenital Cardiac Anomalies

RERE 在先天性心脏异常中的作用

• 批准号: 8769407
• 负责人: Daryl Armstrong Scott
• 金额: $ 7.88万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769407
• 关键词: 1p36; Adult; Affect; Alleles; Apoptosis; Arginine; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiomyopathies; Cardiovascular system; Caring; Cells; Chromosome Deletion; Chromosomes; Clinical; Complex; Congenital Heart Defects; Data; Defect; Deletion Mutation; Development; Dilatation - action; Dipeptides; Disease; Double Outlet Right Ventricle; Embryo; Endocardium; Family; Fibrosis; Foundations; Functional disorder; Gene Expression; Genes; Glutamic Acid; Goals; Heart; Heart Hypertrophy; Heart Septal Defects; Heart failure; Hypertrophy; Individual; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Life; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myocardial; Newborn Infant; Nuclear Receptors; Phenotype; Physicians; Play; Role; Series; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Organisms; Transposition of Great Vessels; Tretinoin; Ventricular Septal Defects; aortic arch; base; cell type; constriction; dosage; heart function; in vivo; interstitial; malformation; mortality; mouse model; novel; postnatal; pressure; prevent; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Our long-term goal is to understand the molecular mechanisms by which disease genes disrupt normal cardiovascular development and function. Cardiovascular malformations and cardiomyopathy are major causes of morbidity and mortality world-wide and are particularly common among the 1:5000 newborns that have terminal or interstitial deletions of chromosome 1p36. The dosage-sensitive genes on chromosome 1p36 that contribute to these cardiac-related problems have yet to be fully elucidated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in a critical region of 1p36 associated with the development of cardiovascular malformations and cardiomyopathy. RERE is a cardiac-expressed nuclear receptor coregulator which positively regulates retinoic acid signaling through its interaction with NR2F2. We have shown that RERE-deficient embryos have aortic arch anomalies, double outlet right ventricle, transposition of the great arteries and perimembranous ventricular septal defects on a C57BL/6 background. We subsequently demonstrated that Rere interacts genetically with Gata4-a retinoic acid-responsive transcription factor encoding gene-during valvular, septal, aortic arch and outflow tract development. In our first specific aim, we will determine if Rere and Gata4 interact genetically in the endocardium to affect the development of the atrioventricular (AV) valvuloseptal complex. This will be accomplished by analyzing the progeny of mice in which Rere and Gata4 have been targeted in the endocardium using a transgenic Tie2-Cre. We will also ablate Rere in the endocardium using the same transgenic Tie2-Cre to determine if expression of RERE in these cells is required for normal AV valvuloseptal development. These experiments are particularly important since valvular and septal anomalies are the most common cardiovascular malformations caused by 1p36 deletions and mutations in GATA4. On a BL6/129S6 background, RERE-deficient mice do not have cardiovascular malformations but spontaneously develop cardiac fibrosis and cardiac hypertrophy. This is consistent with RERE's role as a positive regulator of retinoic acid signaling, which suppresses cardiac fibrosis and myocardial hypertrophy through its actions in cardiomyocytes. However, we cannot eliminate the potential impact of systemic RERE deficiency in the development of these defects using traditional knockout models. To overcome this problem, we generated cardiomyocyte-specific Rere-knockout mice on a mixed background using a transgenic Myh6- Cre. In our second specific aim, we will use these mice to determine RERE's cell-autonomous effects on baseline cardiac function and the heart's response to pressure overload. These studies will lay the foundation from which novel preventative and therapeutic strategies can be developed and tested to help individuals affected by cardiovascular malformations and cardiomyopathy. These studies will also generate mouse models in which clinical interventions can be tested.

描述（由申请人提供）：我们的长期目标是了解疾病基因破坏正常心血管发育和功能的分子机制。心血管畸形和心肌病是世界范围内发病率和死亡率的主要原因，在染色体1 p36末端或间质缺失的1：5000新生儿中尤为常见。染色体1 p36上导致这些心脏相关问题的剂量敏感基因尚未完全阐明。精氨酸-谷氨酸二肽（RE）重复序列基因（RERE）位于与心血管畸形和心肌病发生相关的1 p36关键区域。RERE是一种心脏表达的核受体辅助调节剂，通过与NR 2F 2的相互作用正向调节视黄酸信号传导。 我们已经发现，在C57 BL/6背景下，RERE缺陷的胚胎有主动脉弓异常、右心室双出口、大动脉转位和膜周室间隔缺损。我们随后证明，Rere基因相互作用与Gata 4-视黄酸反应性转录因子编码基因-在瓣膜，间隔，主动脉弓和流出道的发展。在我们的第一个具体目标中，我们将确定Rere和Gata 4是否在内皮细胞中遗传相互作用，以影响房室（AV）瓣膜间隔复合体的发育。这将通过使用转基因Tie 2-Cre分析其中Rere和Gata 4已经在内皮细胞中被靶向的小鼠的后代来实现。我们还将使用相同的转基因Tie 2-Cre消融内膜中的Rere，以确定这些细胞中的RERE表达是否是正常AV瓣间隔发育所需的。这些实验特别重要，因为瓣膜和间隔异常是由GATA 4中的1 p36缺失和突变引起的最常见的心血管畸形。 在BL 6/129 S6背景下，RERE缺陷型小鼠没有心血管畸形，但自发地发生心脏纤维化和心脏肥大。这与RERE作为视黄酸信号传导的正调节剂的作用一致，视黄酸信号传导通过其在心肌细胞中的作用抑制心脏纤维化和心肌肥大。然而，我们不能消除潜在的影响，系统性RERE缺陷的发展，这些缺陷使用传统的敲除模型。为了克服这个问题，我们使用转基因Myh 6- Cre在混合背景上产生了心肌细胞特异性Rere敲除小鼠。在我们的第二个具体目标中，我们将使用这些小鼠来确定RERE对基线心脏功能和心脏对压力超负荷的反应的细胞自主效应。 这些研究将为开发和测试新的预防和治疗策略奠定基础，以帮助受心血管畸形和心肌病影响的个体。这些研究还将产生小鼠模型，可以在其中测试临床干预措施。