GENETICS OF NEUROPEPTIDE Y FUNCTION

描述(申请人摘要)：神经肽Y(NPY)与 食欲和能量平衡的调节，因为(A)集中 注射NPY刺激强健的喂养，(B)NPY的mRNA和蛋白质水平 下丘脑弓状核在还原状态下的升高 能量平衡，以及缺乏瘦素的肥胖小鼠，因此 变得过度吞噬。此外，给药对NPY信号的干预作用 反义寡核苷酸、抗体或NPY受体拮抗剂通常 会抑制进食。因此，这是一个惊喜，基因敲除的小鼠无法使 NPY的体重调节正常。遗传结果清楚地表明 在所检查的条件下，NPY不是喂养所必需的，但它们 没有解决NPY是否强烈参与监管的问题 胃口。神经肽Y的慢性缺失可能会触发代偿性 机械装置。这项提案旨在利用基因技术探索几个 潜在的补偿形式。具体目标包括以下几点 问题：(1)刺鼠相关蛋白(AgRP)对NPY有补偿作用吗 缺乏？(2)弓状核中产生NPY和AgRP的神经元 产生其他可能弥补神经肽Y缺乏的神经调节剂？，和(3) 成人NPY基因表达的急性失活是否会影响食欲和 能量平衡？第一个目标将通过产生小鼠来实现，在其中 NPY和AgRP基因均失活。如果AgRP补偿NPY，那么 这些老鼠应该是瘦的。第二个目标依赖于基因消融 制造NPY和AgRP的神经元。如果这些神经元对能量很重要 平衡，那么这些老鼠应该是瘦的。最后一个目标是通过创建 携带NPY基因的小鼠可以随意灭活。神经肽Y的失活 在成人中的表达可能对调节的短暂或慢性的影响 食欲和能量平衡。这些基因实验应该有助于使 目前通过永久性NPY基因沉默和通过 神经肽Y信号的急性干预。

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.