Interactions between TGFbeta and retinoid signaling in cardiac development

TGFbeta 和类视黄醇信号在心脏发育中的相互作用

• 批准号: 7689941
• 负责人: Loretta L. Jophlin
• 金额: $ 3.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689941
• 关键词: Affect; Animals; Apoptosis; Breeding; Cardiac; Cells; Cessation of life; Childhood; Congenital Heart Defects; Data; Defect; Development; Event; Feedback; Fetal Death; Future; Gene Dosage; Heart; Heart failure; Human; Knock-out; Knockout Mice; Lead; Live Birth; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Neonatal; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Phenocopy; Phenotype; Prevention; Retinoid X Receptor alpha; Retinoids; Role; Secondary to; Signal Transduction; Signaling Molecule; TGFB1 gene; TGFB2 gene; Therapeutic; Tissues; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Work; attenuation; cardiogenesis; cell growth; congenital heart disorder; cytokine; mortality; prevent; public health relevance; research study; therapeutic development

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.

描述（由申请人提供）：先天性心脏缺陷会影响1/200的活产，其中许多缺陷的手术结局差。最近已经显示，在新生儿或小儿期间的手术治疗方法可能导致成年后期的显着发病率和死亡率[1]。为了将来有更好的患者结局，很明显，需要替代疗法来治疗和预防先天性心脏病。为了创建旨在预防或治疗这些缺陷的有用治疗剂，必须发现控制正常和异常心脏发育的分子事件。类维生素性X受体α基因敲除小鼠（RXRA - / - ）表明心脏缺陷是人类先天性心脏病的表征。在这只小鼠中，由于心脏坐垫组织的不易塑性和胎儿死亡，由于心脏衰竭而发生了适当的腔室和流出区（通常）分隔术[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]。心脏发育的关键方面，特别是经常重塑。另外，将研究杂合性对SMAD2和SMADS对RXRA的影响 - / - 将在形态学和分子水平上研究。公共卫生相关性：这些实验将更好地了解控制正常和异常心脏发展的分子事件。我们希望从这些研究中产生的发现将导致最终发展治疗剂，以更好地治疗先天性心脏病。