Regulation of the paracrine angiogenic function of cardiac myocytes by cardiomyoc

描述(由申请人提供)：新的观察表明，心肌细胞生长和心脏血管生成的过程必须在一生中保持平衡，并提示应激反应时心肌肥大和/或心脏血管生成不足会导致心功能受损、心肌病和心力衰竭。心脏生长和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生和发展中发挥重要作用。有趣的是，最近的几项研究表明，心肌细胞本身以旁分泌的方式发挥作用，以调节心脏中血管的生长，以应对压力。然而，对心肌细胞这种旁分泌功能(心肌细胞的血管生成潜能)的分子调控还不是很清楚。我们的中心假设是，在导致心肌肥大的应激条件下，血小板衍生生长因子受体β(PDGFR-1)是心肌细胞血管生成潜力的上游调节因子。为了支持这一假说，我们已经证明，在压力超负荷应激下，心肌细胞特异性PDGFRb基因敲除小鼠会出现心功能障碍、心室扩张和心力衰竭，并与冠状动脉微血管功能缺陷相关。这些发现表明，PDGFR信号是心脏应激反应的一个重要的、迄今未被认识到的中介。为了进一步了解PDGFR信号作为心肌细胞血管生成潜力调节器的作用，我们将使用PDGFRb基因敲除模型，并通过给予靶点包括PDGFR-(Aim One)的抗癌药物，来确定心肌细胞PDGFR信号是否调节冠状动脉血管生成，以应对导致心肌肥大的病理性应激。我们将使用PDGFRb基因敲除模型进一步确定是否需要心肌细胞PDFGR信号来促进冠脉血管生成，这是在出生后早期观察到的生理性心脏生长，还是在成年生活中对运动训练的响应(目标2)。最后，我们将利用一个缺失PDGFR-的体外培养心肌细胞模型来确定PDGFR-信号调节心肌细胞血管生成潜能的机制(S)。通过本申请中提出的实验证实我们的总体假设将表明，心脏中的PDGFR-可能是评估和治疗特定形式的人类心力衰竭的一个新的关注领域，此外，还可能为预防和/或治疗使用针对PDGFR信号转导的药物治疗的癌症患者的心脏毒性提供策略。 公共卫生相关性：本申请中提出的研究将寻求了解血小板衍生生长因子β(PDGFR-)在心脏肌肉生长期间心脏血管生长调节中的作用，PDGFR-是一种表达在包括心肌细胞在内的多种细胞类型的细胞表面的蛋白质，其中一些应激源与心力衰竭的发展直接相关。从这项研究中获得的见解可能被用来开发治疗由多种原因引起的人类心力衰竭的新的治疗策略，也可能有助于开发策略来防止因靶向PDGFR信号转导的抗癌药物而导致的临床心脏毒性。

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. PUBLIC HEALTH RELEVANCE: Studies proposed in this application will seek to understand the role of platelet derived growth factor beta (PDGFR-), a protein expressed on the cell surface of a number of cell types including heart muscle cells, in the regulation of blood vessel growth in the heart during heart muscle growth which occurs as a result of a variety of stressors, some of which are directly linked to the development of heart failure. Insights gained from this study may be used to develop novel therapeutic strategies for the treatment of human heart failure due to multiple etiologies, and may also be useful to help develop strategies to prevent clinical cardiac toxicity due to anti-cancer agents that target PDGFR signaling.