A Novel Class of Orally-Applied Inhibitors of Aggressive Behavior

说明(申请人提供)：多肽YY3-36(PYY3-36)是一种重要的激素，可在餐后从肠道上皮细胞释放到血流中。它的分泌与卡路里摄入量有关，它通过作用于大脑中的Y2受体来诱导饱腹感。最近在PI实验室进行的研究表明，PYY3-36也是由唾液腺分泌的，在调节摄食方面发挥着重要作用。因此，我们的研究最初集中在唾液PYY3-36对食物摄入量的影响。然而，我们偶然地发现，将含有preproPYY的重组病毒载体注射到颌下腺(增加唾液PYY的长期表达)可以消除小鼠的自发攻击，这可能是通过向大脑的边缘和下丘脑区域发出信号来实现的。这项建议的目的是将这一初步发现扩展到实验诱导的攻击行为的大鼠模型，以便我们可以系统地探索潜在的药理学和遗传学方法来治疗人类患者的攻击行为障碍。这项研究将表征迄今为止未知的唾液PYY3-36在调节攻击行为中的功能。 公共卫生相关性：这项提议的目的是表明实验诱导的雄性大鼠唾液中胃肽YY水平的升高减少了它们的自发攻击。这项研究将表征迄今为止未知的唾液PYY3-36在调节攻击行为中的功能。这些研究的成功完成可能导致一种新的治疗应用，用于治疗精神病患者的急性暴力发作。

DESCRIPTION (provided by applicant): Peptide YY3-36 (PYY3-36) is an important hormone that is released post-prandially into the bloodstream from gut epithelial cells. Its secretion is related to caloric intake, and it induces satiety by acting on Y2 receptors in the brain. Recent research conducted in the PI's laboratory indicates that PYY3-36 is also secreted by the salivary glands where it plays a significant role in regulation of feeding. Accordingly, our research originally focused on the impact of salivary PYY3-36 on food intake. However, we serendipitously discovered that injection of a recombinant viral vector containing preproPYY into the submandibular salivary gland (increasing long-term salivary PYY expression) eliminated spontaneous aggression in mice, probably through signaling to limbic and hypothalamic regions of the brain. The objective of this proposal is to extend that initial finding to a rat model of experimentally-induced aggression so that we may systematically explore potential pharmacological and genetic approaches for treatment of aggressive behavior disorders in human patients. The study will characterize the heretofore unidentified functions of salivary PYY3-36 in regulation of aggressive behavior. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to show that experimentally-induced elevated levels of the gastric Peptide YY in saliva of male rat reduce their spontaneous aggression. The study will characterize the heretofore unidentified functions of salivary PYY3-36 in regulation of aggressive behavior. Successful completion of these studies could lead to a novel therapeutic application for the treatment of acute violent outbursts in psychotic patients.