Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8

描述（由申请人提供）：在本补充研究申请中，我们建议扩大我们的项目GM 083926的范围并加快其进展速度，该项目名为“环核苷酸磷酸二酯酶8调节细胞功能”。母基金包含3个具体目标，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PDE同工酶高度表达的三种组织类型。 最近，我们发现PDE8A也在心肌细胞中高度表达。此外，我们的初步数据强烈表明，PDE8的消融可以调节离体心肌细胞中的钙处理。拟定研究的重点是确定PDE8A敲除小鼠的总体心脏表型，并确定PDE8调节心脏钙瞬变的机制。重点将放在PDE8A在控制cAMP依赖性磷酸化事件在分离的心肌细胞中的作用。我们还将研究基因破坏对离体心肌细胞钙调节和体内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。开发基于PDE 8活性调节的抗疟疾药物的可能性似乎是真实的。 公共卫生相关性：在本补充研究申请中，我们建议扩大范围并加快我们的项目GM 083926的进展速度，该项目名为“环核苷酸磷酸二酯酶8对细胞功能的调节”。拟定研究的重点是确定PDE8A敲除小鼠的总体心脏表型，并确定PDE8调节心脏钙瞬变的机制。重点将放在PDE8A在控制cAMP依赖性磷酸化事件在分离的心肌细胞中的作用。我们还将研究基因破坏对体内心脏功能测量的影响。 这些研究可能与心脏功能的药物调节直接相关。例如，如果通过这些研究验证，似乎作为PDE8激活剂的药物可能具有抗肿瘤活性。由于大多数心脏病发作都有心律失常的成分，因此与公共卫生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.