Regulation of cAMP - Dependent Protein Kinase Genes

本研究主要探讨蛋白激酶A（PKA）在调节细胞凋亡中的生理功能。 肥胖、进食和能量消耗。PKA的全酶形式与cAMP相互作用， 磷酸化多种细胞内靶标的活性催化亚基。这一过程是由 支架蛋白（AKAP）和PKA的各种亚型的表达与不同的生化 特性.我的实验室的目标是开发小鼠遗传学方法，可以用来研究 PKA在细胞培养模型中不易操纵的生理途径中的作用。针对性 破坏PKA的RII β调节亚基基因产生了瘦的和抗肥胖的小鼠， 夜间活动增加了两倍这些表型最近被追踪到大脑 我们建议集中精力确定大脑区域和特定的细胞类型， 责任我们还提出了实验来确定激酶活性的变化， 这些表型和潜在的底物。小鼠遗传学在遗传学研究中的应用 对体重调节的研究已经确定了新的激素、神经通路和细胞内信号传导 这些系统都被证明适用于人类。我们的目标是进一步了解 希望这将导致未来的治疗肥胖的相互作用。

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.