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）已与 食欲和能量平衡的调节是因为（a）集中 施用的NPY刺激鲁棒喂养，（b）NPY mRNA和蛋白质水平 在降低的条件下，下丘脑的弧形核心 能量平衡，以及缺乏瘦素的OB/OB小鼠 变得倍率。此外，通过管理NPY信号的干预 通常，抗义寡核苷酸，抗体或NPY受体拮抗剂通常 抑制进食。因此，令人惊讶的是，淘汰小鼠无法做到 NPY的体重调节正常。遗传结果清楚地表明 在检查的条件下，NPY对于进食不是必不可少的，但是它们 不要解决NPY是否急剧参与调节的问题 食欲。慢性缺乏NPY触发了补偿性 机制。该建议旨在使用遗传技术探索几个 潜在的补偿形式。具体目的解决以下 问题：（1）Agouti相关蛋白质（AGRP）是否补偿了NPY 缺乏？，（2）在弧形核中产生NPY和AGRP的神经元是否是否存在 产生其他可能补偿NPY缺乏的神经调节剂？和（3） 成人中NPY基因表达的急性失活会影响食欲和 能量平衡？第一个目标将通过产生小鼠来解决 NPY和AGRP基因都被灭活。如果AGRP补偿了NPY，则 这些老鼠应该瘦。第二个目的依赖于遗传消融 使NPY和AGRP的神经元。如果这些神经元对于能量很重要 平衡，那些老鼠应该瘦。最后一个目标是通过创建来解决的 具有NPY基因的小鼠可以随意失活。 NPY失活 成年人的表达可能对调节 食欲和能量平衡。这些基因实验应有助于合理化 通过永久性NPY基因沉默和通过 NPY信号的急性干预。