Regulation of Coronary Vessel Assembly and Growth

冠状血管组装和生长的调节

• 批准号: 6906581
• 负责人: ROBERT J TOMANEK
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906581
• 关键词: angiogenesis; angiopoietins; biological signal transduction; biomechanics; cardiac myocytes; cardiogenesis; coronary vessels; electron microscopy; enzyme linked immunosorbent assay; fibroblast growth factor; growth factor; growth factor receptors; laboratory mouse; northern blottings; platelet derived growth factor; quail; statistics /biometry; stem cells; vascular endothelial growth factors; vascular endothelium; vertebrate embryology; western blottings

DESCRIPTION (provided by applicant): This proposal will employ quail (Aim 1) and mice (Aim 2-4) to address the overall hypothesis that the continuum of events required to form the hierarchy of the coronary vascular tree requires a complex interplay of cells and molecular signals which are temporally regulated. Experiments in Aim 1 will use in vitro (heart explants) and in ovo approaches to establish the specificity, interactions, and signaling of growth factors that regulate coronary vasculogenesis and angiogenesis during the stages preceding coronary artery formation. Aim 2 will determine the harmonic interplay of growth factors that facilitate postnatal coronary artery growth by examining the assembly, growth and remodeling of the coronary arterial tree. Neutralizing antibodies to growth factors and soluble receptors will be used in Aims 1 and 2 in order to test hypotheses regarding the specific roles of growth factors in various components of the vasculogenic/angiogenic cascade. Aim 3 will address the contribution of bone marrow-derived cells to coronary vessel formation during development. This novel aim tests the hypothesis that these cells are activated by specific growth factors and constitute a second source of precursor cells (the first being the epicardial, subepicardial region) that contribute to early postnatal formation of the coronary vasculature. Finally, Aim 4 addresses cyclic and static stretch, as key players in activating angiogenic growth factors and receptors of both cardiomyocytes and endothelial cells. Three unique features of these studies are that they 1) address the continuum of events constituting the development of the coronary tree and the growth factors which regulate these events, 2) are the first to address bone marrow-derived cells as contributors to the coronary vessels during development, and 3) explore stretch as a growth associated stimulus for myocardial vascularization. Since cardiac development depends on timely and adequate vascularization, an understanding of coronary vasculogenesis and angiogenesis will provide an important foundation for our understanding of cardiac defects.

描述（由申请人提供）：本提案将使用鹌鹑（目标1）和小鼠（目标2-4）来解决总体假设，即形成冠状动脉血管树层次结构所需的连续事件需要细胞和分子信号的复杂相互作用，这些信号是暂时调节的。Aim 1的实验将使用体外（心脏外植体）和体外方法来确定在冠状动脉形成前阶段调节冠状动脉血管生成和血管生成的生长因子的特异性、相互作用和信号传导。目的2将通过检查冠状动脉树的组装、生长和重塑来确定促进出生后冠状动脉生长的生长因子的协调相互作用。针对生长因子和可溶性受体的中和抗体将在目的1和2中使用，以检验关于生长因子在血管生成/血管生成级联的各种组成部分中的特定作用的假设。目的3将讨论骨髓源性细胞在发育过程中对冠状动脉形成的贡献。这一新的目的验证了这样一种假设，即这些细胞被特定的生长因子激活，并构成前体细胞的第二个来源（第一个是心外膜和心外膜下区域），有助于出生后早期冠状动脉血管的形成。最后，Aim 4讨论了循环拉伸和静态拉伸，它们是激活血管生成生长因子和心肌细胞和内皮细胞受体的关键因素。这些研究的三个独特特点是：1)研究了构成冠状动脉树发育的连续事件和调节这些事件的生长因子；2)首次研究了骨髓来源的细胞在冠状血管发育过程中的作用；3)探索了拉伸作为心肌血管形成的生长相关刺激。由于心脏的发育依赖于及时和充分的血管形成，因此对冠状动脉血管生成和血管生成的了解将为我们理解心脏缺陷提供重要的基础。