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
基本信息
- 批准号:7806124
- 负责人:
- 金额:$ 48.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAcuteAdenylate CyclaseAdipocytesAdipose tissueAdrenal CortexAdrenal Cortex HormonesAdrenal GlandsAdultAffectAgonistAldosteroneAnimalsAnti-Arrhythmia AgentsArrhythmiaBlood PressureBrown FatCalciumCardiacCardiac Function StudyCardiac MyocytesCell FractionCell physiologyCellsCholesterol HomeostasisChronicCoupledCouplingCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic NucleotidesDataDrug RegulationsEchocardiographyEnzymesEventFatty acid glycerol estersGenesHeartHeart RateHepatocyteHistocompatibility TestingHormonesImageInstitutesIsoenzymesKnockout MiceL-Type Calcium ChannelsLipidsLipolysisLiverMeasurementMeasuresMediatingMedicineMissionMitochondriaMolecularMusMyocardial InfarctionPathway interactionsPharmaceutical PreparationsPhenotypePhosphorylationProcessProductionPropertyProtein KinasePublic HealthRegulationResearchRoleRyanodine Receptor Calcium Release ChannelRyanodine ReceptorsSarcoplasmic ReticulumSteroidsTelemetryTestingThermogenesisTissuesWorkZona Fasciculataawakebaseexpectationhormone regulationin vivoinhibitor/antagonistparent grantphospholambanphosphoric diester hydrolasepolypeptidepublic health relevanceresponseuptake
项目摘要
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):在本补充研究请求中,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 调节细胞功能”。母基金包含 3 个具体目标,即确定 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在心肌细胞中也高表达。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。拟议研究的重点是确定 PDE8A 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。重点将放在 PDE8A 在控制离体心肌细胞中 cAMP 依赖性磷酸化事件中的作用。我们还将研究基因破坏对离体心肌细胞钙调节和心脏功能体内测量的影响。
普通医学研究所的使命显然与通过调节心脏钙来控制心脏功能的机制研究相关。开发基于 PDE8 活性调节的抗心律失常药物的可能性似乎是相当真实的。
公共健康相关性:在此补充研究请求中,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 调节细胞功能”。拟议研究的重点是确定 PDE8A 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。重点将放在 PDE8A 在控制离体心肌细胞中 cAMP 依赖性磷酸化事件中的作用。我们还将研究基因破坏对心脏功能体内测量的影响。
这些研究可能与心脏功能的药物调节直接相关。例如,如果这些研究得到验证,充当 PDE8 激活剂的药物可能具有抗心律失常活性。由于大多数心脏病发作都有心律失常的成分,因此与公共健康的相关性是显而易见的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph A Beavo的其他文献
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{{ truncateString('Joseph A Beavo', 18)}}的其他基金
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
8303029 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
8303029 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
7941082 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
7781662 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
8118226 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
肌营养不良症中高尔基体相关的 NO-cGMP 信号缺陷
- 批准号:
8516460 - 财政年份:2009
- 资助金额:
$ 48.36万 - 项目类别:
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:
7860273 - 财政年份:2008
- 资助金额:
$ 48.36万 - 项目类别:
Phosphodiesterase 8 Synergies: Regulation of Brown Fat, and Cardiac Functions
磷酸二酯酶 8 协同作用:棕色脂肪和心脏功能的调节
- 批准号:
8510658 - 财政年份:2008
- 资助金额:
$ 48.36万 - 项目类别:
Phosphodiesterase 8 Synergies: Regulation of Brown Fat, and Cardiac Functions
磷酸二酯酶 8 协同作用:棕色脂肪和心脏功能的调节
- 批准号:
8676811 - 财政年份:2008
- 资助金额:
$ 48.36万 - 项目类别:
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:
7525488 - 财政年份:2008
- 资助金额:
$ 48.36万 - 项目类别:
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