Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8

说明(申请人提供)：在这项补充研究请求中，我们建议扩大我们的项目GM083926的范围并加快进度，该项目名为“环核苷酸磷酸二酯酶8对细胞功能的调节”。父母的资助包含三个特定的目标，以确定PDE8在肾上腺、肝脏和棕色脂肪组织中的功能和作用机制。这是该PDE同工酶高度表达的三种组织类型。 最近，我们发现PDE8A在心肌细胞中也有高表达。此外，我们的初步数据有力地表明，消融PDE8可以调节分离的心肌细胞的钙转运。拟议研究的重点将是确定PDE8A基因敲除小鼠的整体心脏表型，并确定PDE8调节心脏钙瞬变的机制(S)。重点介绍PDE8A在控制心肌细胞cAMP依赖的磷酸化事件中的作用。我们还将研究基因中断对分离的心肌细胞钙调节的影响，以及对在体心脏功能测量的影响。 普通医学研究所的使命显然与研究通过调节心脏中的钙来控制心脏功能的机制有关。开发一种基于PDE8活性调节的抗心律失常药物的可能性似乎相当真实。 公共卫生相关性：在这项补充研究请求中，我们建议扩大GM083926项目的范围并加快其进展速度，该项目题为“环核苷酸磷酸二酯酶8对细胞功能的调节”。拟议研究的重点将是确定PDE8A基因敲除小鼠的整体心脏表型，并确定PDE8调节心脏钙瞬变的机制(S)。重点介绍PDE8A在控制心肌细胞cAMP依赖的磷酸化事件中的作用。我们还将研究基因中断对在体心脏功能测量的影响。 这些研究可能与药物对心脏功能的调节直接相关。例如，如果这些研究证实了这一点，那么作为PDE8激活剂的药物可能具有抗心律失常的活性。由于大多数心脏病发作都有心律失常的成分，与公众健康的相关性是显而易见的。

DESCRIPTION (provided by applicant): In this supplementary research request we propose to expand the scope and accelerate the rate of progress on our project GM083926, entitled "Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8". The parent grant contains 3 specific aims, to determine the functions and mechanisms of action of PDE8s in adrenal, liver, and brown fat tissues. These are three of the tissue types in which this PDE isozyme is highly expressed. Recently, we have found that PDE8A is also highly expressed in cardiac myocytes. Moreover, our preliminary data strongly suggest that ablation of PDE8 can modulate calcium handling in isolated cardiocytes. The focus of the proposed studies will be to determine the overall cardiac phenotype of the PDE8A knockout mouse and to identify the mechanism(s) by which PDE8 regulates calcium transients in the heart. Emphasis will be placed on the roles of PDE8A in controlling cAMP dependent phosphorylation events in isolated cardiomyocytes. We will also study the effects of the gene disruption on calcium regulation in isolated cardiomyocytes and on in vivo measurements of cardiac function. The mission of the Institute of General Medicine is clearly relevant to studies on the mechanisms of control of cardiac function by modulation of calcium in the heart. The possibilities for developing an anti-arrhythmic drug based on modulation of PDE8 activity would seem quite real. PUBLIC HEALTH RELEVANCE: In this supplementary research request we propose to expand the scope and accelerate the rate of progress on our project GM083926, entitled "Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8". The focus of the proposed studies will be to determine the overall cardiac phenotype of the PDE8A knockout mouse and to identify the mechanism(s) by which PDE8 regulates calcium transients in the heart. Emphasis will be placed on the roles of PDE8A in controlling cAMP-dependent phosphorylation events in isolated cardiomyocytes. We will also study the effects of the gene disruption on in vivo measurements of cardiac function. These studies are potentially directly relevant to drug regulation of cardiac function. For example, if validated by these studies, it would appear that a drug that acted as a PDE8 activator would likely have anti-arrhythmic activity. Since most heart attacks have an arrhythmia component the relevance to public health is obvious.