Regulation of cAMP - Dependent Protein Kinase Genes

cAMP 依赖性蛋白激酶基因的调节

• 批准号: 7035178
• 负责人: George STANLEY MCKNIGHT
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035178
• 关键词: adipose tissue; bioenergetics; biological signal transduction; body weight; brown fat; cyclic AMP; enzyme structure; gene targeting; genetic regulation; genetically modified animals; laboratory mouse; lipid metabolism; melanocyte stimulating hormone; neurogenetics; neuropharmacology; nutrient intake activity; nutrition related tag; obesity; protein kinase A; psychopharmacology; recombinase; tamoxifen; tissue /cell culture

This proposal is focused on the physiological functions of Protein Kinase A (PKA) in the regulation of adiposity, feeding, and energy expenditure. The holoenzyme form of PKA interacts with cAMP to release active catalytic subunits that phosphorylate a variety of intracellular targets. This process is modulated by scaffolding proteins (AKAPs) and the expression of various isoforms of PKA with different biochemical properties. The goal of my laboratory is to develop mouse genetic approaches that can be used to study the role of PKA in physiological pathways that are not easily manipulated in cell culture models. Targeted disruption of the Rllbeta regulatory subunit gene of PKA creates mice that are lean and resistant to obesity and display a two-fold increase in nocturnal activity. These phenotypes have recently been traced to the brain and we propose to focus our efforts on determining the brain regions and specific cell types that are responsible. We also propose experiments to determine the changes in kinase activity that account for these phenotypes and the potential substrates that are involved. The application of mouse genetics to the study of body weight regulation has identified novel hormones, neural pathways, and intracellular signaling systems that have all proven to be applicable to humans. Our goal is to further understand the signaling interactions in the hope that this will lead to future therapeutic treatments for obesity.

本文着重阐述了蛋白激酶A(PKA)在细胞周期调控中的生理功能。 肥胖、进食和能量消耗。全酶形式的PKA与cAMP相互作用释放 活性催化亚基，可磷酸化多种细胞内靶标。这一过程由以下因素调节 支架蛋白(AKAP)及其不同亚型在不同生化水平的表达 属性。我的实验室的目标是开发小鼠遗传方法，可以用来研究 PKA在细胞培养模型中不易操纵的生理通路中的作用。目标明确 破坏PKA的Rllbeta调节亚单位基因创造出瘦而耐肥胖的小鼠，并 夜间活动增加两倍。这些表型最近被追溯到大脑 我们建议将我们的努力集中在确定大脑区域和特定的细胞类型上 负责任。我们还提出了一些实验，以确定导致这些变化的原因 这些表型和涉及的潜在底物。小鼠遗传学在生物遗传研究中的应用 体重调节的研究发现了新的激素、神经通路和细胞内信号。 已被证明适用于人类的系统。我们的目标是进一步了解信号 相互作用，希望这将导致未来的肥胖症治疗。