Interactions between TGFbeta and retinoid signaling in cardiac development

描述（由申请人提供）：先天性心脏缺陷影响1/200的活产婴儿，其中许多缺陷的手术效果很差。最近有研究表明，在新生儿或儿科时期的手术治疗可导致成年后期显著的发病率和死亡率[10]。为了在未来有更好的患者预后，显然需要替代疗法来治疗和预防先天性心脏病。为了创造有效的治疗方法来预防或治疗这些缺陷，必须揭示控制正常和异常心脏发育的分子事件。维甲酸X受体α敲除小鼠（RXRa-/-）显示心脏缺陷，这是人类先天性心脏病的表型。在这只小鼠中，由于心脏缓冲组织的低可塑性，没有发生适当的腔室和流出道（OFT）分隔，并且在妊娠晚期由于心力衰竭而发生胎儿死亡。转化生长因子β 2 (TGF(32))，一种影响细胞生长、分化和凋亡的细胞因子，在RXRa-/-与野生型（WT）动物[3]的心脏中上调。TGF02信号的增加与RXRa-/-心脏细胞凋亡的增加有关，当在TGFB2背景下繁殖时，这些基因敲除显示OFT分隔缺陷[3]的衰减。这些数据表明，类维甲酸和TGFB通路交叉调节心脏发育，初步研究支持类维甲酸信号传导与TGFB2下游信号分子（即Smad2）之间可能存在直接相互作用[66]。拟议的研究将确定这些相互作用的性质及其在心脏发育中的相关性。我们假设TGFB和类维甲酸信号之间的直接相互作用调节心脏发育的关键方面，特别是OFT重塑。TGFB和类维生素a通路参与者的时空特征将被执行，以确定在RXRa-/-中起作用的任何相关规范反馈机制。此外，Smad2和SmadS杂合性对RXRa-/-的影响将在形态学和分子水平上进行研究。公共卫生相关性：这些实验将更好地理解控制正常和异常心脏发育的分子事件。我们希望，从这些研究中产生的发现将导致治疗方法的最终发展，以更好地治疗先天性心脏病。

DESCRIPTION (provided by applicant): Congenital heart defects affect 1/200 live births and many of these defects have poor surgical outcomes. Recently it has been shown that surgical cures during the neonatal or pediatric period can result in significant morbidity and mortality later in adulthood [1]. In order to have better patient outcomes in the future it is evident that alternate therapies are needed for the treatment and prevention of congenital heart diseases. To create useful therapeutics directed at preventing or treating these defects, the molecular events controlling normal and aberrant heart development must be uncovered. The retinoid X receptor alpha knockout mouse (RXRa-/-) shows cardiac defects which phenocopy human cases of congenital heart disease. In this mouse, proper chamber and outflow tract (OFT) septation does not occur due to hypoplasticity of cardiac cushion tissue and fetal death occurs in late-midgestation due to cardiac failure [2]. Transforming growth factor beta 2 (TGF(32), a cytokine affecting cellular growth, differentiation, and apoptosis is upregulated in the hearts of RXRa-/- versus wild type (WT) animals [3]. This increase in TGF02 signaling is related to increased apoptosis in the RXRa-/- heart and these knockouts, when bred onto a TGFB2 background show an attenuation of OFT septation defects [3]. These data suggest that the retinoid and TGFB pathways intersect to regulate cardiac development and preliminary studies support the potential for direct interaction between retinoid signaling and signaling molecules downstream of TGFB2 (i.e. Smad2) [66]. The proposed study will establish the nature of these interactions and their relevance during heart development. We hypothesize that direct interactions between TGFB and retinoid signaling regulate critical aspects of cardiac development particularly OFT remodeling. Spatial and temporal characterization of TGFB and retinoid pathway players will be performed to determine any relevant canonical feedback mechanisms at work in the RXRa-/-. Additionally, the effects of heterozygosity for Smad2 and SmadS on the RXRa-/- will be investigated on the morphological and molecular levels. Public Health Relevance: These experiments will yield a better understanding of the molecular events controlling normal and aberrant cardiac development. It is our hope that discoveries generated from these studies will lead to the eventual development of therapeutics to better treat congenital heart disease.