Tbx20 regulation of heart valve development

描述（由申请人提供）：先天性心脏瓣膜缺陷是最常见的心脏发育异常之一，可能导致瓣膜退化，在以后的生活中进行手术置换。先天性心脏瓣膜缺陷的根本原因尚不清楚，但细胞外基质（ECM）组分和重塑酶的表达改变与发育性和退行性瓣膜疾病相关。控制心脏瓣膜成熟的候选转录因子是Tbx 20，一种在瓣膜发生期间表达的T-box转录调节蛋白。在心脏发育的早期，Tbx 20促进心肌增殖并抑制成熟。我们假设Tbx 20同样通过减少硫酸软骨素蛋白聚糖（CSPG）和增加MMP表达促进瓣膜细胞增殖并抑制成熟。在转基因小鼠和培养的鸡瓣膜祖细胞中的实验将用于检查Tbx 20在瓣膜发生调节中的正常功能，以及确定Tbx 20活性改变对心脏瓣膜结构和功能的后果。本研究的目的是：1.在体内心脏瓣膜形成过程中操纵Tbx 20功能，以确定改变的Tbx 20活性对心脏瓣膜细胞增殖、ECM组织和重塑的影响。2.鉴定Tbx 20对培养的内膜垫细胞中的细胞增殖、ECM组织和基因表达的近端效应。3.引入基质重塑酶ADAMTS 4和MMP 13的体内表达，以评估受损ECM对瓣膜结构和功能的影响。拟议研究的完成将建立复杂心脏瓣膜结构发展的监管层次。这些研究的长期目标是确定控制正常和异常瓣膜发育的关键调节相互作用，并在成人瓣膜疾病机制中具有潜在应用。在美国，至少有500万人发生心脏瓣膜功能缺陷，并且瓣膜疾病在过去20年中变得越来越常见。越来越多的证据表明，胚胎发育期间表达的瓣膜结构基因在成人疾病期间也受到影响。对瓣膜发育过程的了解的增加在识别先天性心脏病基因以及开发成人瓣膜退行性变的治疗方法方面具有潜在的临床意义。

DESCRIPTION (provided by applicant): Congenital heart valve defects are among the most common cardiac developmental anomalies and can lead to valve degeneration with surgical replacement later in life. The underlying causes of congenital heart valve defects are not well known, but altered expression of extracellular matrix (ECM) components and remodeling enzymes are associated with developmental as well as degenerative valve disease. A candidate transcription factor in the control of heart valve maturation is Tbx20, a T-box transcriptional regulatory protein that is expressed during valvulogenesis. Early in heart development, Tbx20 promotes myocardial proliferation and inhibits maturation. We hypothesize that Tbx20 similarly promotes valve cell proliferation and inhibits maturation by decreasing chondroitin sulfate proteoglycan (CSPG) and increasing MMP expression. Experiments in transgenic mice and cultured chicken valve progenitor cells will be used to examine the normal functions of Tbx20 in the regulation of valvulogenesis as well as to determine the consequences of altered Tbx20 activity on heart valve structure and function. The aims of the research are to: 1. Manipulate Tbx20 function during heart valve formation in vivo to determine effects of altered Tbx20 activity on heart valve cell proliferation, ECM organization and remodeling. 2. Identify proximal effects of Tbx20 on cell proliferation, ECM organization and gene expression in cultured endocardial cushion cells. 3. Introduce expression of matrix remodeling enzymes ADAMTS4 and MMP13, in vivo to assess the effects of compromised ECM on valve structure and function. The accomplishment of the proposed research will establish regulatory hierarchies in the development of complex heart valve structures. The long-term goal of these studies is to identify critical regulatory interactions that control normal and abnormal valve development with potential applications for adult valve disease mechanisms. Heart valve functional defects occur in at least 5 million individuals in the United States and valve disease has become steadily more common over the last 20 years. There is increasing evidence that valve structural genes expressed during embryonic development are also affected during adult disease. The increased understanding of the process of valve development has potential clinical significance in the identification of congenital heart disease genes as well as in the development of therapies for valve degeneration in adults.