GENETICS OF NEUROPEPTIDE Y FUNCTION

描述（申请人摘要）：神经肽Y（NPY）涉及 食欲和能量平衡的调节，因为（a）中央 施用的NPY刺激健壮的进食，（B）NPY mRNA和蛋白质水平 下丘脑弓状核的上升， 能量平衡，以及缺乏瘦素的ob/ob小鼠， 变得贪食此外，通过给予 反义寡核苷酸、抗体或NPY受体拮抗剂通常 抑制进食。因此，令人惊讶的是，敲除小鼠不能使 NPY具有正常的体重调节功能。基因检测结果清楚地表明 NPY在所检查的条件下对于进食不是必需的，但它们 没有解决NPY是否严重参与调节的问题， 胃口这可能是因为长期缺乏神经肽Y触发了代偿性 机制等这项建议旨在利用遗传技术探索几个 可能的补偿方式。具体目标如下 问题：（1）AgRP是否补偿NPY 缺陷？(2)弓状核内产生NPY和AgRP的神经元 产生其他的神经调质来补偿神经肽Y的缺乏？以及（3） 成人NPY基因表达的急性失活是否影响食欲和 能量平衡？第一个目标将通过产生小鼠来实现， NPY和AgRP基因都失活。如果AgRP补偿了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 一种可以随意失活的神经肽Y基因小鼠。NPY失活 在成人中的表达可能对调节 食欲和能量平衡。这些基因实验应该有助于合理化 目前，通过永久性NPY基因沉默和 NPY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.