GENETICS OF NEUROPEPTIDE Y FUNCTION

神经肽 Y 功能的遗传学

• 批准号: 6160020
• 负责人: Richard D. Palmiter
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6160020
• 关键词: appetite; bioenergetics; genetic regulation; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; neurohormones; neuropeptide Y

DESCRIPTION (applicant's abstract): Neuropeptide Y (NPY) has been implicated in the regulation of appetite and energy balance because (a) centrally administered NPY stimulates robust feeding, (b) NPY mRNA and protein levels rise in the arcuate nucleus of the hypothalamus under conditions of reduced energy balance, as well as in ob/ob mice that lack leptin and consequently become hyperphagic. Moreover, intervention of NPY signaling by administering anti-sense oligonucleotides, antibodies or NPY receptor antagonists generally inhibits feeding. Thus, it was a surprise that knock-out mice unable to make NPY had normal body weight regulation. The genetic results clearly indicate that NPY is not essential for feeding under the conditions examined, but they do not address the question of whether NPY is acutely involved in regulation of appetite. It is possible that chronic absence of NPY triggers compensatory mechanisms. This proposal aims to use genetic techniques to explore several potential forms of compensation. The specific aims address the following questions: (1) Does agouti related protein (AgRP) compensate for NPY deficiency?, (2) Do the neurons that make NPY and AgRP in the arcuate nucleus produce other neuromodulators that may compensate for NPY deficiency?, and (3) Does acute inactivation of NPY gene expression in the adult affect appetite and energy balance? The first aim will be addressed by generating mice in which both NPY and AgRP genes are inactivated. If AgRP compensates for NPY, then these mice should be lean. The second aim relies on genetic ablation of the neurons that make NPY and AgRP. If those neurons are important for energy balance, then those mice should be lean. The last aim is addressed by creating mice with a NPY gene that can be inactivated at will. Inactivation of NPY expression in the adult may have transient or chronic effects on regulation of appetite and energy balance. These genetic experiments should help rationalize the current disparate results obtained by permanent NPY gene silencing and by acute intervention of NPY signaling.

描述（申请人的摘要）：神经肽 Y (NPY) 与 食欲和能量平衡的调节，因为（a）集中 施用 NPY 刺激稳健进食，(b) NPY mRNA 和蛋白质水平 下丘脑弓状核在减少的条件下升高 能量平衡，以及缺乏瘦素的 ob/ob 小鼠，因此 变得贪食。此外，通过给予 通常是反义寡核苷酸、抗体或NPY受体拮抗剂 抑制进食。因此，令人惊讶的是，基因敲除小鼠无法制造 NPY 体重调节正常。遗传结果清楚地表明 在所检查的条件下，NPY 对于喂养来说并不是必需的，但它们 没有解决 NPY 是否积极参与监管的问题 食欲。长期缺乏 NPY 可能会引发代偿性反应 机制。该提案旨在利用遗传技术来探索几种 潜在的补偿形式。具体目标涉及以下内容 问题：（1）刺豚鼠相关蛋白（AgRP）是否可以补偿 NPY 缺乏？，（2）弓状核中产生 NPY 和 AgRP 的神经元 产生其他可以弥补 NPY 缺陷的神经调节剂？（3） 成人 NPY 基因表达急性失活是否会影响食欲和食欲？ 能量平衡？第一个目标将通过产生小鼠来解决，其中 NPY 和 AgRP 基因均失活。如果 AgRP 补偿 NPY，那么 这些老鼠应该很瘦。第二个目标依赖于基因消融 产生 NPY 和 AgRP 的神经元。如果这些神经元对于能量很重要 平衡，那么这些小鼠应该是瘦的。最后一个目标是通过创建 带有可随意灭活的NPY基因的小鼠。 NPY 失活 成人中的表达可能对调节产生短暂或慢性影响 食欲和能量平衡。这些基因实验应该有助于合理化 目前通过永久 NPY 基因沉默和通过 NPY信号的急性干预。