CENTRAL PEPTIDERGIC CIRCUITS IN METABOLISM REGULATION

代谢调节中的中枢肽回路

• 批准号: 6196721
• 负责人: TAMAS L HORVATH
• 金额: $ 31.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6196721
• 关键词: Macaca mulatta; biological models; cell cell interaction; cell population study; electron microscopy; fasting; fluorescence microscopy; fos protein; genetic transcription; hormone regulation /control mechanism; hypothalamic hormones; hypothalamus; immunocytochemistry; in situ hybridization; metabolism; model design /development; neural information processing; neural plasticity; neural transmission; neuroendocrine system; neurons; neuropeptide Y; neuroregulation; nutrition related tag; sectioning; synapses

DESCRIPTION (applicant's abstract): In the past decade, an extensive body of experimental evidence has been provided to delineate the hypothalamic component of the regulation of daily energy homeostasis and related autonomic and endocrine mechanisms. However, a great part of our current understanding of human physiology and disorders of metabolism is inferred from rodent models, while little is known about the primate hypothalamic circuits that underlie the appropriate coordination of brain functions in the face of changing environment. In particular, it is ill defined whether the same peptidergic circuits known to be involved in the hypothalamic regulation of rodent homeostasis have similar functions in the primate, including human, brain. Our preliminary experiments have revealed both similarities as well as differences between the interaction of particular hypothalamic peptidergic systems in rats and non-human primates. In order to further clarify the significance of rodent models for primate physiology, we propose to determine and compare the interaction of key hypothalamic peptidergic systems in the non-human primate in relation to metabolic regulation. SPECIFIC AIM 1) In monkeys, we will assess and compare the synaptic input of neuropeptide Y (NPY)-containing hypothalamic cells by axons containing hypocretin/orexin (HCRT), melanin concentrating hormone (MCH), pro-opiomelanocortin (POMC), and agouti gene related peptide (AGRP). SPECIFIC AIM 2) To determine the phenotype of hypothalamic neurons expressing c-fos in response to short-term fasting in non-human primates. SPECIFIC AIM 3) To determine the effect of short-term fasting on hypothalamic expression of NPY-, AGRP-, POMC-, MCH-, and HCRT mRNA in the monkey. Our experiments will provide, for the first time, analysis of gene expression, neuronal activation, and qualitative and quantitative synaptology of hypothalamic peptidergic systems related to metabolic processes in individual monkeys. It should be emphasized that the organization of the rhesus monkey hypothalamus is essentially identical to that of the human. Therefore, it can be inferred that the collected data will be especially pertinent to revise our understanding of the neuroendocrine circuits regulating human metabolism. The need to gain further insights into this central mechanism in humans is particularly timely, since disorders related to metabolism are among the leading cause of health problems in the U.S. with the highest financial consequences on the health care system.

描述（申请人的摘要）：在过去的十年中， 提供了实验证据来描述下丘脑成分 每日能量体内平衡和相关自主神的调节和 内分泌机制。但是，我们目前对 人类生理学和代谢的疾病是从啮齿动物模型中推断出来的 虽然对灵长类动物下丘脑电路知之甚少 面对变化时，脑功能的适当协调 环境。特别是，是否定义了是否相同 已知参与啮齿动物下丘脑调节的电路 体内平衡在灵长类动物中具有相似的功能，包括人，大脑。我们的 初步实验揭示了相似性和差异 在大鼠中特定下丘脑肽系统的相互作用之间 和非人类灵长类动物。为了进一步阐明啮齿动物的重要性 灵长类动物生理的模型，我们建议确定和比较 在非人类灵长类动物中关键下丘脑肽基系统的相互作用 与代谢调节有关。 特定目的1）在猴子中，我们将评估和比较 神经肽Y（NPY） - 含轴突含有下丘脑细胞的轴突 低载素/甲氧素（HCRT），黑色素浓缩激素（MCH），， 促蛋白聚糖素（POMC）和Agouti基因相关肽（AGRP）。 具体目的2）确定表达下丘脑神经元的表型 C-Fos响应非人类灵长类动物的短期禁食。 特定目的3）确定短期禁食对下丘脑的影响 猴子中Npy-，Agrp-，POMC-，MCH-和HCRT mRNA的表达。 我们的实验将首次提供基因表达的分析， 神经元激活以及定性和定量突触学 与个体的代谢过程相关的下丘脑肽基系统 猴子。应该强调的是，恒河猴的组织 下丘脑与人类的下丘脑基本相同。因此，它可以 可以推断收集的数据将与修改我们的 了解调节人类代谢的神经内分泌电路。这 需要进一步了解人类的这种核心机制是 特别及时，由于与代谢有关的疾病是 财务最高的美国健康问题的主要原因 医疗保健系统的后果。