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全世界发病和死亡的主要原因，在 1:5000 染色体 1p36 末端或间质缺失的新生儿中尤其常见。染色体 1p36 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) 重复基因 (RERE) 位于 1p36 的关键区域，与心血管畸形和心肌病的发展相关。 RERE 是一种心脏表达的核受体共调节因子，通过与 NR2F2 相互作用，正向调节视黄酸信号传导。 我们已经证明，RERE 缺陷胚胎在 C57BL/6 背景下具有主动脉弓异常、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，在瓣膜、间隔、主动脉弓和流出道发育过程中，Rere 与 Gata4（一种视黄酸响应转录因子编码基因）存在遗传相互作用。在我们的第一个具体目标中，我们将确定 Rere 和 Gata4 是否在心内膜中通过基因相互作用影响房室 (AV) 瓣膜间隔复合体的发育。这将通过分析使用转基因 Tie2-Cre 将 Rere 和 Gata4 定位于心内膜的小鼠后代来实现。我们还将使用相同的转基因 Tie2-Cre 消融心内膜中的 Rere，以确定这些细胞中 RERE 的表达是否是正常 AV 瓣膜间隔发育所必需的。这些实验尤其重要，因为瓣膜和间隔异常是由 1p36 缺失和 GATA4 突变引起的最常见的心血管畸形。 在 BL6/129S6 背景下，RERE 缺陷的小鼠不会出现心血管畸形，但会自发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是一致的，RERE 通过其在心肌细胞中的作用来抑制心脏纤维化和心肌肥大。然而，我们无法使用传统的敲除模型消除系统性 RERE 缺陷对这些缺陷发展的潜在影响。为了克服这个问题，我们使用转基因 Myh6-Cre 在混合背景下生成了心肌细胞特异性 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 对基线心脏功能的细胞自主效应以及心脏对压力超负荷的反应。 这些研究将为开发和测试新的预防和治疗策略奠定基础，以帮助患有心血管畸形和心肌病的个体。这些研究还将产生可以测试临床干预措施的小鼠模型。