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中，平滑肌基因的从头激活很可能需要SRF这个主调控平台与其他富集的辅助因子形成组合相互作用，以驱动心血管特定基因的活性。虽然SRF在肌原性收缩蛋白基因表达中是必不可少的，但SRF本身不足以调节心血管细胞分化。先前的研究暗示了染色质乙酰化-去乙酰化参与平滑肌基因表达的控制。结合生物信息学预测和实验证据，我们确定了一个新的和重要的HAT，激活新生的平滑肌基因程序。我们提供了多条证据，支持CSRP2BP是一种新型且强大的SRF依赖性平滑肌组蛋白乙酰转移酶的概念，重命名为SM-HAT，可能是控制胚胎平滑肌基因表达和血管平滑肌基因程序和心血管系统形成的核心。这些研究将为心血管的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。本项目的具体目的是：具体目的1：通过小鼠、胚胎干细胞和前心外膜细胞的基因失活来确定SM-HAT的功能。特定目标2：确定SRF和平滑肌富集染色质重塑因子之间共享的机制，SM-HAT特定目标3：确定SRF和平滑肌富集染色质重塑因子之间共享的重叠基因网络，SM-HAT公共卫生相关性：我们确定了一个激活新生平滑肌基因程序的新颖且重要的HAT。我们提供了多条证据，支持CSRP2BP是一种新型且强大的SRF依赖性平滑肌组蛋白乙酰转移酶的概念，重命名为SM-HAT，可能是控制胚胎平滑肌基因表达和血管平滑肌基因程序和心血管系统形成的核心。我们将通过小鼠、胚胎干细胞（ES）细胞和前心外膜细胞的基因失活来确定SM-HAT的功能。我们将定义SRF和SM-HAT之间的共享机制，并确定它们的重叠基因网络。

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.