Regulation of the paracrine angiogenic function of cardiac myocytes bycardiomyoc

心肌细胞旁分泌血管生成功能的调节

基本信息

批准号：
8669059
负责人：
WADIH ARAP
金额：
$ 36.63万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-11-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8669059
关键词：
Adult Aerobic Exercise Angiotensin II Antineoplastic Agents Area Blood Vessels Blood capillaries Cancer Patient Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cell Proliferation Cell surface Clinical Complex Coronary Data Development Dilatation - action Endothelial Cells Equilibrium Etiology Exercise Extracellular Matrix Growth Heart Heart Hypertrophy Heart failure Human Hypertrophy Knock-out Knockout Mice Lead Life Link Mediating Mediator of activation protein Modeling Molecular Muscle Cells Myocardial Myocardium PDGFRB gene Pathologic Pathway interactions Pericytes Physiological Platelet-Derived Growth Factor beta Receptor Play Process Proteins Proto-Oncogene Proteins c-sis Recruitment Activity Regulation Role Signal Transduction Stress Testing Training Tube Ventricular Dysfunction angiogenesis biological adaptation to stress capillary cell type heart preservation in vitro Model insight migration novel novel therapeutics paracrine postnatal pressure prevent research study response role model stressor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Emerging observations indicate that the processes of cardiomyocyte growth and cardiac angiogenesis must remain balanced throughout life and suggest that excess cardiac hypertrophy and/or insufficient cardiac angiogenesis in response to stress leads to impaired cardiac function, cardiomyopathy, and heart failure. An imbalance between cardiac growth and cardiac angiogenesis may play an essential role in the development and progression of multiple forms of human heart failure. Intriguingly, several recent studies indicate that the cardiomyocyte itself functions in a paracrine fashion to regulate blood vessel growth in the heart in response to stress. However, the molecular regulation of this paracrine function of cardiomyocytes (the angiogenic potential of cardiomyocytes) is not well understood. Our central hypothesis is that under conditions of stress that lead to cardiac hypertrophy, platelet derived growth factor receptor beta (PDGFR-) is an upstream regulator of the angiogenic potential of cardiomyocytes. In support of this hypothesis, we have shown that cardiomyocyte specific Pdgfrb knockout mice exposed to pressure overload stress develop cardiac dysfunction, ventricular dilatation and heart failure, associated with defective coronary microvascular function. These findings demonstrate that PDGFR- signaling is an essential and heretofore unappreciated mediator of the cardiac stress response. To further understand the role of PDGFR- signaling as a regulator of the angiogenic potential of cardiomyocytes, we will determine if cardiomyocyte PDGFR- signaling regulates coronary angiogenesis in response to pathologic stressors that lead to cardiac hypertrophy using a Pdgfrb knockout model and also via administration of anti-cancer agents whose targets include PDGFR- (Aim One). We will further determine if cardiomyocyte PDFGR- signaling is required to promote coronary angiogenesis which accompanies physiologic cardiac growth observed in early postnatal life or in adult life in response to exercise training using a Pdgfrb knockout model (Aim Two). Finally, we will determine the mechanism(s) by which PDGFR- signaling regulates the angiogenic potential of cardiomyocytes using an in vitro model of cultured cardiomyocytes in which PDGFR- is deleted. Confirmation of our overall hypothesis through the experiments proposed in this application would suggest that PDGFR- in the heart may be a novel area of concern in evaluating and treating selected forms of human heart failure, and in addition, may inform strategies to prevent and/or treat cardiotoxicity in cancer patients treated with agents that target PDGFR signaling.

描述（由申请人提供）：新出现的观察结果表明，心肌细胞生长和心脏血管生成的过程必须在整个生命过程中保持平衡，并表明应激时过度的心脏肥大和/或心脏血管生成不足会导致心脏功能受损、心肌病和心脏疾病。失败。心脏生长和心脏血管生成之间的不平衡可能在多种形式的人类心力衰竭的发生和进展中发挥重要作用。有趣的是，最近的几项研究表明，心肌细胞本身以旁分泌方式发挥作用，以调节心脏中的血管生长以应对压力。然而，心肌细胞这种旁分泌功能（心肌细胞的血管生成潜力）的分子调节尚不清楚。我们的中心假设是，在导致心脏肥大的应激条件下，血小板衍生生长因子受体β（PDGFR-）是心肌细胞血管生成潜力的上游调节剂。为了支持这一假设，我们已经证明，暴露于压力超负荷应激的心肌细胞特异性 Pdgfrb 敲除小鼠会出现心功能障碍、心室扩张和心力衰竭，与冠状动脉微血管功能缺陷相关。这些发现表明，PDGFR 信号传导是心脏应激反应的重要且迄今为止未被认识到的调节剂。为了进一步了解 PDGFR- 信号传导作为心肌细胞血管生成潜力调节剂的作用，我们将使用 Pdgfrb 敲除模型以及通过施用目标包括 PDGFR-（目标一）的抗癌药物。我们将进一步确定心肌细胞 PDFGR 信号传导是否需要促进冠状动脉血管生成，冠状血管生成伴随出生后早期或成年后观察到的生理性心脏生长，以响应使用 Pdgfrb 敲除模型的运动训练（目标二）。最后，我们将使用删除了 PDGFR- 的体外培养心肌细胞模型来确定 PDGFR- 信号传导调节心肌细胞血管生成潜力的机制。通过本申请中提出的实验证实了我们的总体假设，这表明心脏中的PDGFR-可能是评估和治疗选定形式的人类心力衰竭的一个新的关注领域，此外，还可以为预防和/或预防的策略提供信息。治疗接受针对 PDGFR 信号传导的药物治疗的癌症患者的心脏毒性。