ANIMAL MODELS FOR CARDIOVASCULAR DISEASE

已知生长和分化因子在生长和分化中起调节作用。 心血管对压力和损伤的反应，如肥厚性 心脏和动脉平滑肌对高血压的反应， 血管内皮和平滑肌对损伤的反应 血管成形术，以及心脏的修复和保护反应 和血管系统的疾病 从整体上研究这些反应 在动物水平上，我们有基因工程小鼠， 生长因子、转化生长因子β 1（TGF β 1）和碱性 成纤维细胞生长因子（FGF 2）已被消除或过表达， 分别 TGF β 1缺陷小鼠显示心脏受损 收缩性，血管平滑肌细胞（VSMC）生长异常， 血小板聚集 其中许多表型暗示异常的Ca 2 + 作为缺陷的分子基础进行处理。 FGF 2转基因小鼠 削弱了VSMC的增长。 在这些动物资源中，我们将添加FGF 2 基因敲除小鼠缺乏特定的FGF 2亚型， 在心血管系统中的不同功能作用。 最后我们 将继续开发组织特异性或条件性敲除方案 以便仅在动物的特定组织中消除基因功能。 通过这些动物模型，我们将研究i）TGF β 1在 调节心肌细胞中的Ca 2+流动，ii）TGF β 1和FGF 2的作用 在心脏肥大的发展过程中， 肌肉蛋白亚型，iii）TGF β 1在血小板中的调节作用 功能，iv）FGF 2和TGF β 1在缺血中的保护作用- 再灌注损伤，v）微脉管系统的发育，和vi）生长 去内皮化后血管平滑肌和内皮的控制。 整体动物、整体器官和离体细胞的生理学方法 水平将包括超声多普勒心动图，工作表现和 Langendorff全心制备物，离体心脏细胞力学，Ca 2 + 瞬态测量，和单离子通道记录和VSMC， 内皮细胞培养 共同调节因子的表达改变 TGF β和FGF以及下游效应物的心血管功能 TGF β 1、FGF β 1和GGF 2的水平。 通过这些研究，我们 将获得关于生长因子在以下方面的作用的更明确的信息： 收缩性，心脏和VSMC肥大，缺血-再灌注损伤， 新生血管形成、动脉损伤和血小板功能障碍。

Growth and differentiation factors are known to play regulatory roles in the cardiovascular response to stress and injury, such as the hypertrophic response of cardiac and arterial smooth muscle to hypertension, the response of vascular endothelium and smooth muscle to injury after angioplasty, and also in the repair and protective responses of the heart and vasculature to ischemic attack. To study these responses at the whole animal level, we have genetically engineered mice in which two of these growth factors, transforming growth factor beta-1 (TGFbeta1) and basic fibroblast growth factor (FGF2) have been ablated or overexpressed, respectively. The TGFbeta1-deficient mouse displays impaired cardiac contractility, abnormal vascular smooth muscle cell (VSMC) growth, and poor platelet aggregation. Many of these phenotypes implicate abnormal Ca2+ handling as the molecular basis of the defects. The transgenic FGF2 mouse has impaired VSMC growth. To these animal resources we will add FGF2 knockout mice which are deficient in specific FGF2 isoforms thought to play differential functional roles in the cardiovascular system. Finally, we will continue to develop tissue-specific, or conditional, knockout schemes in order to ablate gene function only in specific tissues of the animal. With these animal models we will investigate i) the role of TGFbeta1 in regulating Ca2+ flux in cardiomyocytes, ii) the roles of TGFbeta1 and FGF2 in the development of cardiac hypertrophy and the resulting switch in muscle protein isoforms, iii) the regulatory role of TGFbeta1 in platelet function, iv) the protective roles of FGF2 and TGFbeta1 in ischemia- reperfusion injury, v) development of microvasculature, and vi) growth control in vascular smooth muscle and endothelium after de-endothelization. Physiological approaches at the whole animal, whole organ and isolated cell levels will include echo Doppler cardiography, work-performing and Langendorff whole heart preparations, isolated cardiac cell mechanics, Ca2+ transient measurements,a nd single ion channel recordings and VSMC and endothelial cell culture. Altered expression of factors that co-regulate cardiovascular functions with TGFbeta and FGF, and of downstream effectors of TGFbeta1 and FGFbeta1 and GGF2 will be measured. With these studies we will obtain more definitive information on the roles of growth factors in contractility, cardiac and VSMC hypertrophy, ischemia-reperfusion injury, neovascularization, arterial injury, and platelet dysfuncTIon.