Peptide Receptor Systems

肽受体系统

• 批准号: 7594518
• 负责人: Ted B Usdin
• 金额: $ 157.97万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594518
• 关键词: Animals; Anxiety; Behavior; Brain; Brain region; Emotional; Emotions; Evaluation; FOS gene; Genes; Genetic; Goals; Immediate-Early Genes; In Vitro; Investigation; Knockout Mice; Laboratories; Lead; Life; Maps; Moods; Mus; Neuroanatomy; Neuroendocrinology; Neuromodulator; Neurons; Neuropeptides; Parathyroid Hormone Receptor 2; Peptide Receptor; Peptides; Physiological; Series; Sex Behavior; Site-Directed Mutagenesis; Stimulus; Symptoms; System; Techniques; Transgenic Mice; base; behavioral pharmacology; fast-acting neurotransmitter; gene replacement; genetic manipulation; male; receptor; research study; therapeutic target; tuberoinfundibular peptide 39

A current major focus of the laboratory is investigation of the physiological function of the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) and its receptor the parathyroid hormone 2 (PTH2) receptor, which were discovered in this laboratory several years ago. Using site directed mutagenesis and bacterial expression we developed a highly selective and potent peptide antagonist of the PTH2 receptor. We have completed an in vitro characterization of the antagonist and are now ready to proceed with experiments using it in living animals. We are in the midst of a series of experiments aimed at identifying the situations and stimuli that lead to activation of the TIP39-PTH2 receptor system. One completed experiment that uses immunohistochemical colocalization of the immediate early gene c-fos and TIP39 demonstrates that TIP39 containing neurons are activated in association with male sexual behavior. We have obtained mice with genetic replacement of the gene for TIP39 by a marker gene. We have performed a comprehensive study of the distribution of TIP39 and a detailed comparison with the distribution of the PTH2 receptor in mouse brain using these transgenic mice. Based on the presence of TIP39 and the PTH2 receptor in brain regions involved in emotional function we have created TIP39 null mice and initiated a set of experiments comparing the behavior of wild-type and TIP39 knockout mice with a focus on anxiety-related behaviors.

该实验室目前的主要工作重点是研究该实验室几年前发现的39个残基的神经肽结节漏斗肽（TIP39）及其受体甲状旁腺激素2（PTH2）受体的生理功能。 通过定点诱变和细菌表达，我们开发了一种高度选择性且有效的 PTH2 受体肽拮抗剂。我们已经完成了拮抗剂的体外表征，现在准备在活体动物中进行使用它的实验。 我们正在进行一系列实验，旨在确定导致 TIP39-PTH2 受体系统激活的情况和刺激。 一项使用立即早期基因 c-fos 和 TIP39 的免疫组织化学共定位完成的实验表明，含有 TIP39 的神经元被激活与男性性行为相关。 我们已经获得了用标记基因对 TIP39 基因进行遗传替换的小鼠。 我们使用这些转基因小鼠对小鼠大脑中 TIP39 的分布进行了全面的研究，并与 PTH2 受体的分布进行了详细的比较。 基于涉及情绪功能的大脑区域中 TIP39 和 PTH2 受体的存在，我们创建了 TIP39 缺失小鼠，并启动了一系列实验，比较野生型和 TIP39 敲除小鼠的行为，重点关注与焦虑相关的行为。