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，可导致瓣膜变性，并在以后的生活中进行手术置换。先天性心脏瓣膜缺陷的潜在原因尚不清楚，但细胞外基质（ECM）成分和重塑酶的表达改变与发育性和退行性瓣膜疾病有关。控制心脏瓣膜成熟的一个候选转录因子是Tbx20，这是一个在瓣膜发生过程中表达的T-box转录调节蛋白。在心脏发育早期，Tbx20促进心肌增殖，抑制心肌成熟。我们假设Tbx20同样通过降低硫酸软骨素蛋白多糖（CSPG）和增加MMP表达来促进瓣膜细胞增殖和抑制成熟。在转基因小鼠和培养的鸡瓣膜祖细胞中，我们将研究Tbx20在调节瓣膜发生中的正常功能，以及Tbx20活性改变对心脏瓣膜结构和功能的影响。本研究的目的是：1。在体内调节Tbx20在心脏瓣膜形成过程中的功能，以确定Tbx20活性改变对心脏瓣膜细胞增殖、ECM组织和重塑的影响。2. 确定Tbx20对培养心内膜缓冲细胞增殖、ECM组织和基因表达的近端影响。3. 在体内引入基质重塑酶ADAMTS4和MMP13的表达，评估ECM受损对瓣膜结构和功能的影响。这项研究的完成将在复杂心脏瓣膜结构的发展中建立调控等级。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控相互作用，并潜在地应用于成人瓣膜疾病机制。在美国，至少有500万人患有心脏瓣膜功能缺陷，在过去的20年里，瓣膜疾病变得越来越普遍。越来越多的证据表明，在胚胎发育期间表达的瓣膜结构基因也会在成人疾病期间受到影响。对瓣膜发育过程的进一步了解对先天性心脏病基因的鉴定以及成人瓣膜变性治疗的发展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.