Genetic Reduction in Peptide Amidation Results in Neuroendocrine Deficits

肽酰胺化的基因减少导致神经内分泌缺陷

• 批准号: 7541358
• 负责人: Danielle Bousquet Moore
• 金额: $ 2.68万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541358
• 关键词: Acute; Adenoviruses; Affect; Amino Acid Sequence; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Ascorbic Acid; Behavior; Biochemical Reaction; Biological; Boxing; C-Peptide; Copper; Diazepam; Diet; Dietary Copper; Disease; Electroconvulsive Shock; Embryo; Epilepsy; Exposure to; Fluoxetine; Genetic; Goals; Histologic; Hormones; Human; Hypersensitivity; Hypothalamic structure; Immunohistochemistry; Injection of therapeutic agent; Malnutrition; Menkes Kinky Hair Syndrome; Mind; Modeling; Mus; Mutation; Neuraxis; Neuropeptides; Neurosecretory Systems; Obesity; Pair Bond; Pentylenetetrazole; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Physiological Processes; Post-Translational Protein Processing; Reaction; Recovery; Role; Seizures; Selective Serotonin Reuptake Inhibitor; Signaling Molecule; Site; Supplementation; System; Testing; Thermogenesis; Viral; Week; Western Blotting; Wild Type Mouse; amidation; ascorbate; genetic manipulation; hypocupremia; improved; intraperitoneal; mouse model; natural hypothermia; peptide hormone; receptor; research study; response; restoration

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

描述(申请人提供)：100多个肽作为细胞间信号分子在中枢神经系统(CNS)发挥作用。小鼠体内特定多肽的遗传操作/缺失已将多肽与各种生理功能联系在一起，如焦虑、癫痫敏感性、配对结合和肥胖(11；14；22；23)。一种翻译后修饰，？-酰胺化，是赋予超过一半的神经肽和多肽激素生物活性所必需的(15；16)。酰胺化反应只能通过肽甘氨酸酰胺化单加氧酶(PAM)(12)催化的酶反应进行。PAM基因缺失会导致胚胎死亡(12)。如果没有足够的铜和抗坏血酸(维生素C)，PAM催化的反应就不可能发生。人类必须从饮食中获得铜和抗坏血酸。因此，这项建议的目标是使用PAM杂合子(PAM)小鼠来识别对有限的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突变或饮食缺乏铜或维生素C对肽能酰胺化影响的生理过程。PAM的病毒替代，铜的药理补充/耗尽，以及特定多肽的输送将被用来挽救或加剧已确定的生理缺陷。知道了PAM小鼠模型中对缺乏肽能酰胺化最敏感的生理过程和行为，然后就有可能将这些观察扩展到人类。由于PAM的遗传缺陷或饮食中铜和抗坏血酸缺乏导致的有限酰胺化在焦虑障碍、癫痫障碍和神经内分泌障碍中的作用可以在人类中进行评估。