Genetic Reduction in Peptide Amidation Results in Neuroendocrine Deficits

描述（由申请人提供）：超过100多肽在整个中枢神经系统（CNS）中作为细胞间信号分子起作用。小鼠体内特定肽的基因操作/删除将肽与各种生理功能联系起来，如焦虑、癫痫敏感性、配对结合和肥胖（11;14;22;23）。一个翻译后修饰？-酰胺化是赋予一半以上的神经肽和肽激素生物活性所必需的（15;16）。酰胺化仅通过肽基甘氨酸催化的酶促反应发生？-酰胺化单氧酶（PAM）（12）。PAM基因缺失导致胚胎致死（12）。如果没有足够的铜和抗坏血酸（维生素C）， PAM催化的反应就不能发生。人类必须从饮食中获得铜和抗坏血酸。因此，本课题的目标是利用小鼠杂合PAM （PAM）来鉴定对有限肽能酰胺化最敏感的生理系统。在PAM小鼠中发现的缺陷将确定最有可能受到PAM突变或饮食中铜或维生素C缺乏对肽能酰胺的影响的生理过程。病毒替代PAM，药理学补充/铜的消耗，以及特定肽的递送将用于挽救或加剧已确定的生理缺陷。了解PAM小鼠模型中对缺乏肽能酰胺最敏感的生理过程和行为，将有可能将这些观察扩展到人类。由于PAM基因缺乏或饮食中铜和抗坏血酸缺乏而引起的有限酰胺化在焦虑症、癫痫和神经内分泌疾病中的作用，可以在人类中进行评估

DESCRIPTION (provided by applicant): More than 100 peptides function throughout the central nervous system (CNS) as intercellular signaling molecules. Genetic manipulation/deletion of specific peptides in mice has connected peptides to various physiological functions, such as anxiety, seizure sensitivity, pair bonding and obesity (11;14;22;23). One posttranslational modification, ?-amidation, is necessary to confer biological activity to more than half of the neuropeptides and peptide hormones (15; 16). Amidation only occurs through the enzymatic reaction catalyzed by peptidylglycine ?-amidating monooxgenase (PAM) (12). Genetic deletion of PAM results in embryonic lethality (12). The reaction catalyzed by PAM cannot occur without adequate levels of copper and ascorbic acid (vitamin C). Humans must obtain both copper and ascorbic acid from their diets. Thus, the goal of this proposal is to use mice heterozygous for PAM (PAM) to identify the physiological systems that are most sensitive to limited peptidergic amidation. Deficits identified in PAM mice will identify the physiological processes most likely to be affected by mutations in PAM or by the effects of dietary deficiencies in copper or vitamin C on peptidergic amidation. Viral replacement of PAM, pharmacological supplementation/depletion of copper, and delivery of specific peptides will be used to rescue or exacerbate the physiological deficits identified. Knowing the physiological processes and behaviors most sensitive to lack of peptidergic amidation in the PAM mouse model, it will then be possible to extend these observations to humans. A role for limited amidation due to a genetic deficiency in PAM or dietary deficiencies in copper and ascorbate in anxiety disorders, seizure disorders and neuroendocrine disorders can then be assessed in humans