ANGIOTENSIN II AND PDGE AND CARDIAC DEVELOPMENT

已经确定了几种内在的和外在的 包括生长因子和机械负荷在内的刺激相互作用 通过心脏的遗传程序来调节正常和 病理性心脏分化和生长。机械式 心肌细胞的负荷可能有一个内在的起源，即 心肌细胞收缩的力量的结果，也可能导致 从与血流动力学效应相关的外力 血液流动的速度。心肌细胞和血液的收缩 心流在发展的早期阶段就开始了。机械载荷是 已知可增加旁分泌生长因子的释放 还可以增加心肌细胞收缩的速度和力度。 机械负荷和一些生长因素进一步影响 心肌细胞和间质组织生长和 辨证是决定心脏的主要因素 发展和功能。这项拨款建议利用老鼠 在文化系统中，它将考察 肌细胞分化、机械负荷与二次生长 血管紧张素II(Ang II)与血小板源性生长 因子(PDGF)。这项提议的主要目标是 通过添加对早期胚胎小鼠进行实验操作 血管紧张素Ⅱ和血小板衍生生长因子对正常和转基因动物培养的影响 和细胞来确定这些生长因子在早期的作用 心脏发育。具体目标是：1)建立 本实验室建立的小鼠全胚胎培养系统及 血管紧张素转换酶II和血小板衍生生长因子的时间和空间效应 正常和转基因小鼠心肌细胞和心脏 2)利用对齐的心肌细胞培养体系 机械张力对培养的正常和转基因小鼠的作用 测定Ang II、PDGF与心肌细胞间的相互作用 机械负荷；3)建立客观的形态计量学分析方法 评估肌细胞形态和肌原纤维结构 组织。

It has been established that several intrinsic and extrinsic stimuli, including growth factors and mechanical load, interact with the genetic program f the heart to regulate normal and pathological cardiac differentiation and growth. Mechanical loading of cardiac myocytes may have an intrinsic origin as a result of the force of myocyte contraction and may also result from the extrinsic forces associated with the hemodynamic effects of blood flow. Both contraction of cardiac myocytes and blood flow begin at an early stage in development. Mechanical load is known to increase the paracrine release of growth factors which also increases the rate and force of myocyte contraction. Mechanical loading and some growth factors further influence cardiac myocyte and interstitial tissue growth and differentiation which are primary factors in determining heart development and function. This grant proposes to utilize mice in culture systems which will examine the relationships between myocyte differentiation, mechanical loading and two growth factors, angiotensin II (Ang II) and platelet derived growth factor (PDGF). The primary goals of this proposal are to experimentally manipulate early embryonic mice by the addition of Ang II and PDGF to cultures of normal and transgenic animals and cells to determine the role of these growth factors in early cardiac development. The specific aims are to: 1) establish the mouse whole embryo culture system in our laboratory and to determine the temporal and spatial effects of Ang II and PDGF on normal and transgenic mouse cardiac myocyte and heart differentiation; 2) use the aligned myocyte culture system to apply mechanical tension to cultured normal and transgenic mouse myocytes to determine the interaction between Ang II, PDGF and mechanical load; and 3) develop an objective morphometric assay to assess myocyte shape and myofibrillar structure and organization.