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结果很差。最近的研究表明，在新生儿或儿童时期进行手术治疗可能会导致成年后的显著发病率和死亡率[1]。为了在未来获得更好的患者结局，显然需要替代疗法来治疗和预防先天性心脏病。为了创造预防或治疗这些缺陷的有用疗法，必须揭示控制正常和异常心脏发育的分子事件。类维生素A X受体α基因敲除小鼠（RXRa-/-）表现出心脏缺陷，其表型与人类先天性心脏病病例相似。在这只小鼠中，由于心脏垫组织的可塑性减退，没有发生适当的腔室和流出道（OFT）分隔，并且由于心力衰竭，胎儿死亡发生在妊娠中期晚期[2]。转化生长因子β 2（TGF β 2），一种影响细胞生长、分化和凋亡的细胞因子，在RXR α-/-动物的心脏中相对于野生型（WT）动物上调[3]。TGF β 2信号传导的这种增加与RXR α-/-心脏中细胞凋亡的增加有关，并且当在TGF β 2背景上繁殖时，这些敲除显示出OFT分隔缺陷的减弱[3]。这些数据表明，类维生素A和TGFB通路交叉调节心脏发育，初步研究支持类维生素A信号传导和TGFB 2下游信号传导分子（即Smad 2）之间直接相互作用的可能性[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过程中的相关性。我们假设TGFB和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。将进行TGFB和类维生素A通路参与者的空间和时间表征，以确定在RXRa-/-中起作用的任何相关规范反馈机制。此外，将在形态学和分子水平上研究Smad 2和SmadS的杂合性对RXRa-/-的影响。公共卫生相关性：这些实验将产生一个更好的理解的分子事件控制正常和异常的心脏发育。我们希望这些研究的发现将最终导致更好地治疗先天性心脏病的治疗方法的发展。

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.