Mechanism of Drug-Induced Adenylyl Cyclase Super-Sensitization
药物诱导腺苷酸环化酶超敏化机制
基本信息
- 批准号:7944152
- 负责人:
- 金额:$ 27.48万
- 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 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAdenylate CyclaseAffectBehaviorBiochemical ProcessBiological ModelsCellsChronicComplexCyclic AMP ReceptorsData SetDegradation PathwayDependenceDevelopmentDiseaseDrug AddictionEnzymesFollow-Up StudiesGenesHeterotrimeric GTP-Binding ProteinsHormonalIndividualLaboratoriesMediatingMolecularNeuronsPathway interactionsPhosphorylationPhosphotransferasesProcessProtein KinaseProteinsRecoveryResistanceRing Finger DomainRoleSignal PathwaySiteSmall Interfering RNASpecificityUbiquitinUnited StatesWithdrawalWorkaddictionadenylyl cyclase type Vbasedrug mechanismdrug of abusegenome-widehigh throughput screeninginsightnovelprotein degradationreceptorreceptor couplingreconstitutionresponseubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Drug addiction is a devastating disease affecting millions of people in the United States. At the core of this behavior are complex biochemical processes that affect individual neurons and neuronal circuits. A major challenge is to understand the molecular and cellular basis of addiction and associated behaviors of dependence, withdrawal, tolerance, and sensitization. Many abused drugs act directly or indirectly on receptors that in turn activate the Gi/Go class of heterotrimeric G proteins and upon chronic stimulation of these receptors, the cAMP signaling pathway is up-regulated. An early adaptive response to chronic Gi stimulation is an increase in the activity of adenylyl cyclase termed adenylyl cyclase super-sensitization. Studies over the years have provided a great deal of information regarding the molecular basis responsible for adenylyl cyclase super-sensitization and have implicated the involvement of many of the regulators of adenylyl cyclase, including Gs1, Gi1, 23, and protein kinases; however, the major mechanisms underlying this phenomenon is still largely unknown. My laboratory has developed a cell based model system for of adenylyl cyclase super-sensitization that is amenable to moderate high throughput screening approaches. This work has allowed us to develop and execute a genome wide siRNA screen to identify genes that when silenced, block the adenylyl cyclase super-sensitization that develops in response to chronic hormonal activation of a Gi pathway. We will examine the phosphorylation of adenylyl cyclase that occurs during adenylyl cyclase super- sensitization (aim 1), study the role of TTK, a dual-specificity protein kinase protein that we identified in our screen in the development of the super-sensitivity of the adenylyl cyclase enzyme (aim 2). Our results from the siRNA screen, as well as follow up studies implicate a role of protein turnover in the development of adenylyl cyclase super-sensitization; aim 3 of the proposal examines the role of the ubiquitin-mediated protein degradation pathway in adenylyl cyclase super-sensitization. In aim 4 we will characterize the role of an identified AKAP target of the ubiquitin-mediated protein turnover machinery in the development of adenylyl cyclase super-sensitization. Our genome-wide siRNA screen has produced a rich dataset that will provide us with a unique opportunity to identify novel components of the signaling pathways that underlie adenylyl cyclase super-sensitization. This will provide insights into the biologically important process of drug addiction.
描述(由申请者提供):毒瘾是一种毁灭性的疾病,在美国影响着数百万人。这种行为的核心是影响单个神经元和神经元回路的复杂生化过程。一个主要的挑战是了解成瘾的分子和细胞基础以及相关的依赖、戒断、耐受和敏化行为。许多滥用药物直接或间接作用于受体,进而激活Gi/Go类异源三聚体G蛋白,在这些受体的慢性刺激下,cAMP信号通路上调。对慢性胃肠道刺激的早期适应性反应是腺酰环化酶活性的增加,称为腺酰环化酶超敏化。多年来的研究已经提供了大量关于腺酰环化酶超敏化的分子基础的信息,并涉及许多腺酰环化酶调节因子的参与,包括GS1、Gi1、23和蛋白激酶;然而,这种现象背后的主要机制在很大程度上仍然不清楚。我的实验室已经开发了一个基于细胞的腺酰环化酶超敏化模型系统,该系统适用于中高通量的筛选方法。这项工作使我们能够开发和执行全基因组的siRNA筛选,以确定当沉默时,阻断腺苷环化酶超敏化的基因,腺苷环化酶是对GI途径的慢性激素激活做出的反应。我们将研究在腺酰环化酶超敏化过程中发生的腺酰环化酶的磷酸化(目标1),研究TTK的作用,TTK是我们在筛选中发现的一种双特异性蛋白激酶蛋白,在腺酰环化酶超敏感性的发展中(目标2)。我们从siRNA筛选以及后续研究的结果表明,蛋白质周转在腺酰环化酶超敏化的发展中起着作用;该提案的目标3检查了泛素介导的蛋白质降解途径在腺酰环化酶超敏化中的作用。在目标4中,我们将表征泛素介导的蛋白质周转机制中已识别的AKAP靶标在腺酰环化酶超敏化发展中的作用。我们的全基因组siRNA筛选已经产生了丰富的数据集,这将为我们提供一个独特的机会来识别构成腺苷环化酶超级敏化的信号通路的新成分。这将为了解毒瘾这一生物学上重要的过程提供洞察力。
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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RONALD TAUSSIG其他文献
RONALD TAUSSIG的其他文献
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{{ truncateString('RONALD TAUSSIG', 18)}}的其他基金
ANALYSIS OF HORMONE REGULATED ADENYLYCYCLASE ISOFORMS
激素调节的腺苷酸环化酶异构体的分析
- 批准号:
6285066 - 财政年份:1996
- 资助金额:
$ 27.48万 - 项目类别:
ANALYSIS OF HORMONE REGULATED ADENYLYCYCLASE ISOFORMS
激素调节的腺苷酸环化酶异构体的分析
- 批准号:
6682924 - 财政年份:1996
- 资助金额:
$ 27.48万 - 项目类别:
ANALYSIS OF HORMONE REGULATED ADENYLYCYCLASE ISOFORMS
激素调节的腺苷酸环化酶异构体的分析
- 批准号:
6490093 - 财政年份:1996
- 资助金额:
$ 27.48万 - 项目类别:
ANALYSIS OF HORMONE REGULATED ADENYLYCYCLASE ISOFORMS
激素调节的腺苷酸环化酶异构体的分析
- 批准号:
6705043 - 财政年份:1996
- 资助金额:
$ 27.48万 - 项目类别:
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