Regulation of cAMP - Dependent Protein Kinase Genes

描述（由申请人提供）：本提案的总体目标之一是了解PKA信号在调节摄食和能量消耗的神经元通路中的作用。小鼠遗传技术使我们能够在生理环境中研究这个问题，也为我们提供了在分子水平上定义调控的新工具。我们建议使用小鼠遗传方法来检测和定量下丘脑中已知参与体重调节和对脂肪源性激素瘦素反应的神经元特异性mRNA调控。除了检测转录的变化外，我们还将研究预先存在的mrna的翻译控制的潜在作用。最近的工作继续挑战和扩展我们对体重的神经控制的看法。瘦素受体已被证明以神经元特定的模式参与多种信号通路，这些信号系统之间的串扰，包括cAMP/PKA通路，是一个需要更全面探索的新途径。RII2 KO小鼠系很瘦，对饮食引起的肥胖有抵抗力，我们最近的研究结果表明，这是由于大脑中瘦素敏感性的增加。本研究的具体目的是：(1)确定PKA活性在瘦素敏感性和体重调节中发挥作用的下丘脑神经元；(2)测定特定下丘脑神经元中多体相关mrna对饮食和瘦素的响应变化；(3)确定RII2 KO小鼠瘦素敏感性增加的机制。下丘脑反应网络对瘦素的敏感性是决定有多少能量被储存为脂肪的最终决定因素之一，而瘦素抵抗是肥胖的决定性特征之一。

DESCRIPTION (provided by applicant): One of the overall goals of this proposal is to understand the role of PKA signaling in the neuronal pathways that regulate feeding and energy expenditure. Mouse genetic techniques allow us to investigate this problem in a physiological setting and also provide us with novel tools for defining regulation at the molecular level. We propose to use a mouse genetic approach to detect and quantities neuron-specific mRNA regulation in regions of the hypothalamus known to be involved in body weight regulation and the response to the adipose derived hormone, leptin. In addition to detecting changes in transcription we will examine the potential role of translational control of pre-existing mRNAs. Recent work has continued to challenge and expand our views on the neural control of body weight. Leptin receptors have been shown to engage multiple signaling pathways in a neuron specific pattern and the crosstalk between these signaling systems, including the cAMP/PKA pathway, is a new avenue that needs to be explored more comprehensively. The RII2 KO mouse line is lean and resistant to diet-induced obesity and our recent results indicate that this is because of an increase in leptin sensitivity in the brain. The specific aims of this proposal are: (1) Identify the hypothalamic neurons in which PKA activity plays a role in leptin sensitivity and body weight regulation (2) Assay changes in polysome-associated mRNAs in specific hypothalamic neurons in response to diet and leptin (3) Determine the mechanism of increased leptin sensitivity in RII2 KO mice. The sensitivity of the hypothalamic response network to leptin is one of the ultimate determinants of how much energy is stored as fat and leptin resistance is one of the defining features of obesity.