ANGIOTENSIN II AND PDGE AND CARDIAC DEVELOPMENT

已经确定，一些内在和外在的 刺激，包括生长因子和机械负荷，相互作用 心脏的基因程序来调节正常的， 病理性心脏分化和生长。 机械 心肌细胞的负荷可能有内在的起源， 这是肌细胞收缩力的结果，也可能导致 与血液动力学效应相关的外力 血液流动。心肌细胞和血液的收缩 流动开始于发育早期阶段。 机械负载 已知增加生长因子的旁分泌释放， 也增加了肌细胞收缩的速率和力量。 机械负荷和一些生长因子进一步影响 心肌细胞和间质组织生长， 分化是决定心脏的主要因素 发展和功能。 这项资助计划利用老鼠 在文化系统中， 肌细胞分化、机械负荷和二次生长 因子、血管紧张素II（Ang II）和血小板源性生长 因子（PDGF）。 本提案的主要目标是 实验性地操作早期胚胎小鼠， Ang II和PDGF对正常和转基因动物培养物的影响 和细胞来确定这些生长因子在早期 心脏发育 具体目标是：1）建立 小鼠全胚胎培养系统， 确定Ang II和PDGF在时间和空间上的作用， 正常和转基因小鼠心肌细胞和心脏 分化; 2）使用对齐的肌细胞培养系统， 对培养的正常和转基因小鼠施加机械张力 心肌细胞，以确定血管紧张素II，PDGF和 机械负荷;和3）开发客观的形态测定法 评估肌细胞形状和肌原纤维结构， organization.

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.