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）：新兴观察结果表明，心肌细胞生长和心脏血管生成的过程必须在整个生命中保持平衡，并表明心脏肥大过多和/或心脏血管生成响应压力会导致心脏功能受损，心脏疾病，心肌疾病和心脏失败。心脏生长与心脏血管生成之间的失衡可能在多种形式的人类心力衰竭的发展和发展中起着至关重要的作用。有趣的是，最近的一些研究表明，心肌细胞本身以旁分泌方式起作用，以调节心脏中的血管生长，以应对压力。然而，尚不清楚心肌细胞（心肌细胞的血管生成潜力）的这种旁分泌功能的分子调节。我们的中心假设是，在导致心脏肥大的压力条件下，血小板衍生的生长因子受体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，我们表明心肌细胞特异性PDGFRB敲除小鼠暴露于压力过载压力应力会出现心脏功能障碍，心室扩张和心力衰竭，与缺陷的冠状动脉微血管功能有关。这些发现表明，PDGFR信号传导是心脏应力反应的必不可少的，迄今为止未欣赏的介体。为了进一步了解PDGFR信号作为心肌细胞的血管生成潜力的调节剂的作用，我们将确定心肌细胞PDGFR信号是否会调节冠状动脉生成，以响应病理胁迫，以响应通过A PDGFRB敲除模型和Antimant of Antig-cants的pd canters-prfr的pdgfrb contiacter prophy的病理胁迫（响应心脏肥大）（均应）。我们将进一步确定心肌细胞PDFGR-信号是否需要促进冠状动脉血管生成，冠状动脉血管生成伴随着生理性心脏增长在产后早期生活或成人生活中，以响应使用PDGFRB敲除模型（目标二）进行运动训练。最后，我们将确定PDGFR信号传导使用培养的心肌细胞的体外模型来调节心肌细胞的血管生成潜力的机制，其中删除了PDGFR-。通过本应用中提出的实验确认我们的总体假设将表明，心脏中的PDGFR-可能是评估和治疗所选形式的人类心力衰竭形式的新型领域，此外，还可能为预防和/或治疗针对PDGFR信号的药物治疗的癌症患者中的心脏毒性提供了信息。