Role of Neuronal PKA Signaling in Energy Homeostasis

神经元 PKA 信号传导在能量稳态中的作用

• 批准号: 9467788
• 负责人: Jonathan Carter Bean
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2020-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467788
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Agonist; Appetite Depressants; Appetite Stimulants; Attenuated; Body Weight decreased; Chronic; Coronary Arteriosclerosis; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dependence; Designer Drugs; Desire for food; Development; Dominant-Negative Mutation; Energy Metabolism; Epidemic; Fasting; Feeding behaviors; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genes; Genetic Translation; Glutamates; Homeostasis; Hormones; Hyperphagia; Hypertension; Hypothalamic structure; Leptin; Ligands; Melanocortin 4 Receptor; Messenger RNA; Monitor; Mus; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Oxytocin Receptor; Pathway interactions; Peptides; Peripheral; Pharmacology; Phenotype; Phosphodiesterase Inhibitors; Phosphotransferases; Physiological; Play; Polyribosomes; Population; Pro-Opiomelanocortin; Production; Protein Inhibition; Protein Subunits; Publishing; Regulation; Research Proposals; Research Technics; Role; Signal Pathway; Signal Transduction; Stroke; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Therapeutic; Translating; United States; Viral; Virus; Weight; Weight Gain; Work; alternative treatment; antagonist G; feeding; fight against; follow-up; ghrelin; high risk; inhibitor/antagonist; inward rectifier potassium channel; neural circuit; neuromechanism; neuroregulation; novel; obesity treatment; paraventricular nucleus; postsynaptic; preference; presynaptic; protein activation; receptor; relating to nervous system; response; therapeutic target; transcriptome sequencing

Project Summary Obesity has reached epidemic levels in the United States in recent years. Understanding the neural mechanisms underlying feeding behavior has thus become a critical undertaking. Although we are beginning to get a better understanding of the neural circuits that control energy homeostasis, the intracellular signaling mechanisms remain relatively unknown. Long term control over feeding behavior involves a hypothalamic circuit. Pro- opiomelanocortin (POMC), and agouti related peptide (AgRP) neurons in the arcuate nucleus respond to peripheral hormones including leptin and ghrelin and then signal to the melanocortin receptor 4 (MC4R) neurons in the paraventricular hypothalamic nucleus (PVH) to control energy homeostasis. This proposal seeks to determine the role of Protein Kinase A (PKA) within this pathway. I will virally express a Cre dependent dominant negative RIα subunit of PKA, AAV-flex-RIαB-mCherry, or Cre dependent Gαs coupled designer receptor activated by designer drugs (DREADD), AAV-flex-GsD-mCherry, in AgRP-Cre expressing mice. These state-of- the-art techniques will allow us to determine the effect of suppressing or stimulating PKA on feeding behavior. By combining our previously developed technique of immunoprecipitating polyribosomes (RiboTag) we will also be able to examine the role of PKA signaling in nutritionally regulated mRNA translation in AgRP neurons. Further studies will utilize the RIB and GsD expressing virus to determine what role PKA plays in the response of MC4R-Cre expressing neurons to the MC4R ligand, MSH. The PKA signaling pathway is well suited to pharmacological manipulation by agonists and antagonists of G-protein coupled receptors, phosphodiesterase inhibitors, and kinase activators and inhibitors. Our proposal seeks to identify potential targets within hypothalamic neurons that might be exploited to modulate feeding behavior as a therapeutic approach to the treatment of obesity.

项目摘要 近年来，肥胖症在美国已经达到了流行病的程度。了解神经机制 因此，潜在的进食行为成为一项关键任务。虽然我们开始得到更好的 了解控制能量稳态的神经回路，细胞内信号传导机制 仍然相对未知。对进食行为的长期控制涉及下丘脑回路。亲- 弓状核中的阿黑皮素（POMC）和阿格列汀相关肽（AgRP）神经元对 外周激素包括瘦素和生长激素释放肽，然后向黑皮质素受体4（MC 4 R）神经元发出信号 在室旁下丘脑核（PVH）控制能量稳态。这项建议旨在 确定蛋白激酶A（PKA）在该途径中的作用。我将病毒性表达Cre依赖的显性基因 PKA负RIα亚基、AAV-flex-RIαB-mCherry或Cre依赖性Gαs偶联设计受体 在表达AgRP-Cre的小鼠中，通过设计药物（DREADD）AAV-flex-GsD-mCherry激活。这些国家- 现有技术将允许我们确定抑制或刺激PKA对进食行为的影响。 通过结合我们以前开发的免疫沉淀多聚核糖体（RiboTag）技术，我们还将 能够检查PKA信号传导在AgRP神经元中营养调节的mRNA翻译中的作用。进一步 研究将利用表达RI β B和GsD的病毒来确定PKA在免疫应答中的作用。 MC 4 R-Cre表达神经元对MC 4 R配体，MC 4 R-MSH。PKA信号通路非常适合于 G蛋白偶联受体磷酸二酯酶激动剂和拮抗剂的药理学操作 抑制剂和激酶激活剂和抑制剂。我们的建议旨在确定潜在的目标， 下丘脑神经元，可能被利用来调节摄食行为作为一种治疗方法， 治疗肥胖症。