Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8

环核苷酸磷酸二酯酶 8 对细胞功能的调节

• 批准号: 7806124
• 负责人: Joseph A Beavo
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806124
• 关键词: Ablation; Acute; Adenylate Cyclase; Adipocytes; Adipose tissue; Adrenal Cortex; Adrenal Cortex Hormones; Adrenal Glands; Adult; Affect; Agonist; Aldosterone; Animals; Anti-Arrhythmia Agents; Arrhythmia; Blood Pressure; Brown Fat; Calcium; Cardiac; Cardiac Function Study; Cardiac Myocytes; Cell Fraction; Cell physiology; Cells; Cholesterol Homeostasis; Chronic; Coupled; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Drug Regulations; Echocardiography; Enzymes; Event; Fatty acid glycerol esters; Genes; Heart; Heart Rate; Hepatocyte; Histocompatibility Testing; Hormones; Image; Institutes; Isoenzymes; Knockout Mice; L-Type Calcium Channels; Lipids; Lipolysis; Liver; Measurement; Measures; Mediating; Medicine; Mission; Mitochondria; Molecular; Mus; Myocardial Infarction; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Process; Production; Property; Protein Kinase; Public Health; Regulation; Research; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Steroids; Telemetry; Testing; Thermogenesis; Tissues; Work; Zona Fasciculata; awake; base; expectation; hormone regulation; in vivo; inhibitor/antagonist; parent grant; phospholamban; phosphoric diester hydrolase; polypeptide; public health relevance; response; uptake

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.

描述（由申请人提供）：在这份补充研究申请中，我们建议扩大范围并加快我们的项目GM083926的进展速度，该项目名为“环核苷酸磷酸二酯酶8调节细胞功能”。父母资助有三个具体目标，确定PDE8s在肾上腺、肝脏和棕色脂肪组织中的功能和作用机制。这是三种PDE同工酶高度表达的组织类型。