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Regulation of Coronary Vessel Assembly and Growth

冠状血管组装和生长的调节

基本信息

批准号：
7244281
负责人：
ROBERT J TOMANEK
金额：
$ 34.96万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244281
关键词：
3-Dimensional Address Angiogenic Factor Aorta Blood Vessels Blood capillaries Bone Marrow Cardiac Cardiac Myocytes Cell Proliferation Cells Complex Concept Formation Congenital Heart Defects Coronary Coronary Vessels Coronary artery Data Development Embryonic Heart Endothelial Cells Endothelium Event Family member Fibroblast Growth Factor Foundations Genes Goals Growth Growth Factor Growth Factor Interaction Growth Factor Receptors Heart In Vitro Laboratories Life Mechanics Metabolic Molecular Mus Myocardial Penetration Platelet-Derived Growth Factor Play Process Quail Regulation Role Sea Signal Transduction Smooth Muscle Myocytes Source Specificity Staging Stem cells Stimulus Stretching System Testing Trees Tube Tubular formation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascularization Work angiogenesis arterial remodeling autocrine base capillary cardiogenesis in vivo inhibitor/antagonist migration neutralizing antibody novel paracrine postnatal precursor cell receptor research study response vasculogenesis

项目摘要

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（由申请方提供）：本提案将采用鹌鹑（目标1）和小鼠（目标2-4）来解决总体假设，即形成冠状血管树层次结构所需的连续事件需要时间调节的细胞和分子信号的复杂相互作用。目标1中的实验将使用体外（心脏外植体）和卵内方法来建立在冠状动脉形成之前的阶段调节冠状动脉血管发生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和谐相互作用。将在目的1和2中使用生长因子和可溶性受体的中和抗体，以检验关于生长因子在血管生成/血管生成级联反应的各种组分中的特定作用的假设。目的3将阐述骨髓源性细胞在发育过程中对冠状动脉血管形成的贡献。这一新的目标测试的假设，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，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，目标4解决了循环和静态拉伸，作为激活心肌细胞和内皮细胞的血管生成生长因子和受体的关键球员。这些研究的三个独特特征是：1）解决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）首次解决了骨髓源性细胞在发育期间对冠状动脉血管的贡献，3）探索了拉伸作为心肌血管化的生长相关刺激。由于心脏的发育依赖于及时和充分的血管化，了解冠状动脉血管发生和血管生成将为我们了解心脏缺陷提供重要的基础。