The Role of BMP-10 in Cardiac Development

描述（由申请方提供）：哺乳动物妊娠中期 胚胎发育（E9.5-E15.5），新形成的胚胎心脏是 需要在细胞数量和大小上快速增长，并经历一系列的 形态和功能的变化，以应对不断增加的体积， 循环血液增殖的心肌细胞形成一个明显的松散的 心肌纤维的交织网，即所谓的心室小梁， 在E9.5心室腔。到E14.5，这些小梁结构变得更多 向心外膜表面致密，小梁间隐窝 变成毛细血管。小梁形成的显著减少与 与心肌生长停滞相关，导致早期胚胎发育 杀伤力另一方面，生长活性的异常增强， 心肌导致心肌致密化失败，这可能是 严重小儿心脏病的原因，心室致密化不全 人类的肌肉萎缩症然而，人们对潜在的 分子和细胞机制。最近，我们发现， 转化生长因子β超家族，骨形态发生蛋白-10 骨形成蛋白10（BMP 10）可能是一种新的参与心肌细胞凋亡的肽类生长因子。 心室小梁形成和致密化。这 该提案旨在验证我们的假设，即BMP-10对 心脏生长和心室小梁致密化， 体内分析。我们建议：1）评估BMP-10在增强 用两种心肌细胞生长试验检测胚胎心肌细胞增殖， 体外; 2）确定心肌细胞增殖的BMP-10依赖性; 3） 通过体外培养BMP-10基因，分析其在心脏发育中的作用。 4）使用转基因小鼠进一步确定BMP-10的作用; approach.我们相信，我们的努力将有助于进一步了解 心脏发育和某些形式的先天性心脏缺陷。

DESCRIPTION (provided by applicant): During the midgestation of mammalian embryonic development (E9.5-E15.5), the newly formed embryonic heart is required to grow rapidly in cell number and size and undergoes a series of morphological and functional changes in response to the increasing volume of circulating blood. The proliferating cardiomyocytes form a distinct loose interwoven meshwork of myocardial fibers, the so-called ventricular trabeculae, in E9.5 ventricular chambers. By E14.5, these trabecular structures become more compact toward the epicardial surface, and the intertrabecular recesses are reduced to capillaries. The significant reduction of trabeculation is closely associated with the myocardium growth arrest that leads to an early embryonic lethality. On the other hand, the abnormal enhancement of growth activity of myocardium leads to the failure of myocardial compaction, which is likely the cause of a severe pediatric cardiac disease, Noncompaction of the Ventricular Myocardium, in humans. However, there is little known about the underlying molecular and cellular mechanism. Recently, we found that a member of transforming growth factor beta superfamily, Bone Morphogenetic Protein-10 (BMP10), may be a novel peptide growth factor involved in the cardiac ventricular trabeculation and compaction during the midgestation stages. This proposal is designed to test our hypothesis that BMP-l0 is critical to the cardiac growth and ventricular trabeculation-compaction using both in vitro and in vivo analyses. We propose to: 1) Assess the role of BMP-10 in enhancing embryonic cardiomyocyte proliferation using two cardiomyocyte growth assays in vitro; 2) Determine the BMP-10 dependency of cardiomyocyte proliferation; 3) Analyze the role of BMP-10 in cardiac development by generating BMP-10- deficient mice; 4) Further define the role of BMP-10 using a transgenic approach. We believe that our effort will shed light on further understanding of cardiac development and some forms of congenital cardiac defects.