TRH and Energy Homeostasis

TRH 和能量稳态

• 批准号: 6899416
• 负责人: RONALD Michael LECHAN
• 金额: $ 21.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899416
• 关键词: bioenergetics; brain mapping; cell population study; genetically modified animals; green fluorescent proteins; hormone regulation /control mechanism; laboratory mouse; leptin; neural information processing; neuroendocrine system; paraventricular nucleus; suid alphaherpesvirus 1; thyrotropin releasing hormone; transfection /expression vector

DESCRIPTION (provided by applicant): Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy homeostasis not only through effects on thyroid function, but also on feeding behavior, thermogenesis, and autonomic regulation. We hypothesize that two distinct populations of TRH-producing neurons located in the medial/periventricular vs anterior parvocellular subdivision of the hypothalamic paraventricular nucleus (PVN) have critical roles in a coordinated effort to mediate the effects of TRH on energy homeostasis. To determine how these two TRH neuronal populations are integrated into energy control systems in the brain and elucidate their specific functions, we will develop transgenic mice in which Cre recombinase is selectively targeted to TRH-producing cells. This approach, together with the use of genetically modified pseudorabies virus (PRV) that exploits the Cre-loxP system for conditional replication and expression of the fluorescent marker protein, GFP, will be used to elucidate the complex, multisynaptic circuitries regulating of each of these neuronal groups and their regulation by leptin. In addition, using Cre-lox-site-specific recombination, we propose to construct a PRV derivative that is dependent on a Cre-mediated recombination event for replication, yet unable to infect other adjacent or transsynaptic neuronal populations due to a mutation in gB, a major membrane protein required for membrane fusion and transneuronal passage of virions. Thus, only neurons that express Cre will be targeted for cell death, allowing selective loss of the TRH neuronal population in each defined anatomical region of the PVN without any effects on adjacent populations. The use of these novel "suicide" viruses to selectively ablate TRH neurons in each subdivision of the PVN, will ultimately allow the elucidation of the full gambit of physiologic effects exerted by TRH neurons in the anterior vs medial/periventricular subdivision in the regulation of energy homeostasis, and may become of general value as a new neuroanatomical tool for neuroscience research.

描述（由申请人提供）：促甲状腺激素释放激素（TRH）在能量稳态调节中具有重要作用，不仅通过影响甲状腺功能，而且还通过影响摄食行为、产热和自主调节。我们假设，位于下丘脑室旁核 (PVN) 的内侧/室周与前小细胞细分中的两个不同的产生 TRH 的神经元群体在协调调节 TRH 对能量稳态的影响方面发挥着关键作用。为了确定这两个 TRH 神经元群如何整合到大脑的能量控制系统中并阐明它们的特定功能，我们将开发转基因小鼠，其中 Cre 重组酶选择性地靶向产生 TRH 的细胞。这种方法与利用 Cre-loxP 系统进行条件复制和荧光标记蛋白 GFP 表达的转基因伪狂犬病病毒 (PRV) 一起，将用于阐明调节这些病毒的复杂的多突触回路。神经元群及其瘦素的调节。此外，利用Cre-lox位点特异性重组，我们建议构建一种PRV衍生物，该衍生物依赖于Cre介导的重组事件进行复制，但由于gB突变而无法感染其他相邻或跨突触神经元群体，膜融合和病毒粒子跨神经元通过所需的主要膜蛋白。因此，只有表达 Cre 的神经元才会成为细胞死亡的目标，从而允许 PVN 每个定义的解剖区域中的 TRH 神经元群体选择性丢失，而不会对相邻群体产生任何影响。使用这些新型“自杀”病毒选择性地消融 PVN 每个细分中的 TRH 神经元，最终将能够阐明前部与内侧/心室周围细分中的 TRH 神经元在能量调节中所产生的完整生理效应稳态，并且可能作为神经科学研究的新神经解剖工具具有普遍价值。