Tbx20 regulation of heart valve development

Tbx20对心脏瓣膜发育的调节

• 批准号: 7389567
• 负责人: Katherine E Yutzey
• 金额: $ 36.41万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389567
• 关键词: Adult; Affect; Animals; Binding; Biochemical; Biological Assay; Birds; Boxing; Cardiac; Cartilage; Cell Proliferation; Cells; Chickens; Chondroitin Sulfate Proteoglycan; Collagen; Complex; Defect; Deposition; Development; Disease; Ectopic Expression; Embryo; Embryonic Development; Enzymes; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression; Genes; Goals; Heart; Heart Valves; Human; Individual; Lead; Life; Limb structure; Localized; Matrix Metalloproteinases; Metalloproteinase Gene; Molecular; Morphogenesis; Mus; Mutagenesis; Myocardial; Operative Surgical Procedures; Physiological; Process; Proteins; Proteoglycan; Proteolysis; Regulation; Regulatory Element; Relative (related person); Reporting; Research; Research Personnel; Role; Staging; Stem cells; Stratification; Structural Genes; Structure; Tendon structure; Transcription Regulatory Protein; Transgenic Mice; Transgenic Organisms; Tube; United States; aggrecan; aggrecanase; cardiogenesis; clinically significant; congenital heart disorder; genetic regulatory protein; in vivo; inhibitor/antagonist; malformation; programs; research study; therapy development; transcription factor

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.

描述(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和退行性瓣膜疾病有关。控制心脏瓣膜成熟的候选转录因子是Tbx20，它是一种T-box转录调节蛋白，在瓣膜形成过程中表达。在心脏发育早期，Tbx20促进心肌增殖，抑制成熟。我们推测Tbx20同样通过减少硫酸软骨素蛋白多糖(CSPG)和增加基质金属蛋白酶的表达来促进瓣膜细胞的增殖和抑制细胞的成熟。在转基因小鼠和培养的鸡瓣膜祖细胞上进行的实验将用于检测Tbx20在调节瓣膜形成方面的正常功能，以及确定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.在活体心脏瓣膜形成过程中调控Tbx20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.研究Tbx20对培养的心内膜垫细胞增殖、ECM组织及基因表达的影响。3.引入基质重塑酶ADAMTS4和MMP13的体内表达，评价受损ECM对瓣膜结构和功能的影响。这项拟议研究的完成将在复杂心脏瓣膜结构的发展中建立监管层级。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常见。越来越多的证据表明，在胚胎发育过程中表达的瓣膜结构基因在成人疾病中也会受到影响。加强对瓣膜发育过程的了解，对于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具有潜在的临床意义。