The Role of Cysteine Rich Protein2 Binding Protein in Cardiovascular Development

描述(由申请人提供)：在心血管系统的早期规范期间，平滑肌基因的从头激活很可能需要SRF(主调节平台)与其他丰富的辅助因子形成组合相互作用，以驱动心血管特定的基因活性。尽管SRF对于肌源性收缩蛋白基因的表达是必不可少的，但单靠SRF还不足以调节心血管细胞的分化。以往的研究表明染色质乙酰化-去乙酰化参与了对平滑肌基因表达的调控。结合生物信息学预测和实验证据，我们确定了一种新的和重要的HAT，它激活了新生平滑肌基因计划。我们提供了多条证据支持CSRP2BP是一种新的和强大的依赖于SRF的平滑肌组蛋白乙酰转移酶，更名为SM-HAT可能是控制胚胎平滑肌基因表达和可能的血管平滑肌基因程序和心血管系统形成的中枢。这些研究将为心血管发展和疾病提供新的见解，并将推进心血管系统的再生和修复策略。本项目的具体目标是：特定目标1：通过基因失活在小鼠、胚胎干细胞和心外膜前细胞中确定SM-HAT的功能(S)。特异目的2：明确SRF与平滑肌富含染色质重塑因子的共同机制，SM-HAT特异目的3：确定SRF与平滑肌富含染色质重塑因子SM-HAT共有的重叠基因网络，SM-HAT与公共卫生相关：我们鉴定了一个新的重要的HAT，激活新生平滑肌基因计划。我们提供了多条证据支持CSRP2BP是一种新的和强大的依赖于SRF的平滑肌组蛋白乙酰转移酶，更名为SM-HAT可能是控制胚胎平滑肌基因表达和可能的血管平滑肌基因程序和心血管系统形成的中枢。我们将通过在小鼠、胚胎干细胞和心外膜前细胞中的基因失活来确定SM-HAT的功能(S)。我们将定义SRF和SM-HAT之间共享的机制，并确定它们重叠的基因网络。

DESCRIPTION (provided by applicant): De novo activation of smooth muscle genes during the early specification of the cardiovascular system very likely requires SRF, the master regulatory platform, to form combinatorial interactions with other enriched co-factors to drive cardiovascular specified gene activity. Although SRF is indispensable for myogenic contractile protein gene expression, SRF alone is not sufficient for regulating cardiovascular cell differentiation. Previous studies implicated the involvement of chromatin acetylation-deacetylation in the control of smooth muscle gene expression. Combining bioinformatic predictions and experimental evidence, we identified a novel and important HAT that activates the nascent smooth muscle gene program. We provided multiple lines of evidence that support the concept that CSRP2BP is a novel and powerful SRF dependent Smooth Muscle Histone Acetyl-Transferase, renamed SM-HAT may be central for controlling embryonic smooth muscle gene expression and possibly vascular smooth muscle gene programs and the formation of the cardiovascular system. These studies will provide new insights in cardiovascular development and disease, and will advance strategies for regeneration and repair of the cardiovascular system. The specific aims of this project are: Specific Aim 1: To determine the function(s) of SM-HAT by gene inactivation in mice, embryonic stem (ES) cells and pro-epicardial cells. Specific Aim 2: To define the mechanisms shared between SRF and the smooth muscle enriched chromatin remodeling factor, SM-HAT Specific Aim 3: To Identify the overlapping gene networks shared between SRF and the smooth muscle enriched chromatin remodeling factor, SM-HAT PUBLIC HEALTH RELEVANCE: We identified a novel and important HAT that activates the nascent smooth muscle gene program. We provided multiple lines of evidence that support the concept that CSRP2BP is a novel and powerful SRF dependent Smooth Muscle Histone Acetyl-Transferase, renamed SM-HAT may be central for controlling embryonic smooth muscle gene expression and possibly vascular smooth muscle gene programs and the formation of the cardiovascular system. We will determine the function(s) of SM-HAT by gene inactivation in mice, embryonic stem (ES) cells and pro-epicardial cells. We will define the mechanisms shared between SRF and SM-HAT and Identify their overlapping gene networks.