The Role of BMP-10 in Cardiac Development

描述(申请人提供)：哺乳类动物中期 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 形态和功能的变化，以响应不断增加的体积 血液循环。增殖的心肌细胞形成明显的疏松 心肌纤维的交织网络，即所谓的室小梁， 在E9.5脑室。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 变成了毛细血管。骨小梁的显著减少与 与导致早期胚胎的心肌生长停滞有关 杀伤力。另一方面，细菌生长活性的异常增强 心肌致密化失败，很可能是 一种严重的儿童心脏病的病因--心室致密化不全 人体内的心肌。然而，人们对其背后的原因知之甚少 分子和细胞机制。最近，我们发现一名成员 转化生长因子β超家族，骨形态发生蛋白-10 (BMP10)，可能是一种新的心脏多肽生长因子。 妊娠中期的脑室小梁和致密化。这 该提案旨在测试我们的假设，即BMP-10对 体外和体外心脏生长和脑室小梁紧实术 活体分析。我们建议：1)评估BMP-10在促进 应用两种心肌细胞生长试验检测胚胎心肌细胞增殖 2)测定BMP-10对心肌细胞增殖的依赖性；3) 通过产生BMP-10来分析BMP-10在心脏发育中的作用 缺陷小鼠；4)通过转基因进一步确定BMP-10的作用 接近。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.