OPIATE PEPTIDES AND RECEPTORS IN THE FAT/FAT MICE

脂肪/脂肪小鼠中的阿片肽和受体

• 批准号: 2625476
• 负责人: L Y BERMAN
• 金额: $ 11.64万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2625476
• 关键词: autoradiography; brain metabolism; carboxypeptidase; developmental neurobiology; disease /disorder model; dosage; drug metabolism; dynorphins; enkephalins; enzyme deficiency; genetically modified animals; in situ hybridization; laboratory mouse; neurotransmitter agonist; neurotransmitter antagonist; nutrient intake activity; nutrition related tag; obesity; opioid receptor; point mutation; radioimmunoassay; receptor binding

The candidate, Dr. Yemiliya Berman, holds a Ph.D. degree from the Institute of Molecular Biology, Moscow, Russia. She is a Research Assistant Professor in the Department of Pharmacology at the New York University Medical Center. The long-term career goals will be to gain an understanding of opioid peptides and their involvement in modulating physiological functions. New York University Medical Center and R. L. Devi's laboratory provides the intellectual environment necessary for the development of a strong research program. In addition, Dr. L. Devi will advise and guide the candidate to become an independent scientist, committed to a productive biomedical research career. The candidate's career goal is to investigate the role of the opioid system in a mouse model for obesity fat/fat. This mouse model is deficient in carboxypeptidase E, an enzyme involved in the maturation of opioid peptides and a regulated secretory pathway sorting receptor. In the brain of fat/fat mice there is a large decrease in fully processed opioid peptides and a large increase in the level of COOH- terminal extended peptides, high molecular weight dynorphin containing peptides and unprocessed prodynorphin. In this grant application the regional distribution of ir-dynorphin and ir-enkephalin peptides and mRNA levels in adult and developing brains of fat/fat mice will be examined (specific aim 1). These studies will provide information on the differential distribution and developmental variations in the levels of opioid peptides. The effect of changes in the levels of dynorphin peptides on the opiate receptor system will be examined in adult and developing fat/fat mice (specific aim 2). Total receptor number and agonist stimulated GTP [g-35S] binding will be measured by autoradiography and adenylyl cyclase activity will be used for functional quantification of microns, delta and kappa opioid receptors. These studies will help to understand how the opiate receptor system adapt to incomplete peptide processing. The hypothesis that impaired Prodynorphin processing in the fat/fat mice is a result of incorrect sorting and secretion in an unregulated manner will be evaluated (specific aim 3). These studies will provide information on how CPE obliteration leads to incomplete Prodynorphin processing and release abnormalities. The responsiveness of fat/fat and lean littermate mice to microns, delta and kappa agonists and antagonists in terms of their feeding behavior will be examined (specific aim 4). Agonists or antagonists will be administered acutely and cumulative food intake in the one hour following injection will be determined. Dose response curves will be generated. These studies will provide information on opioid receptor types involved in feeding of fat/fat mice and development of obesity.

候选人Yemiliya Berman博士拥有博士学位。学位 分子生物学研究所，俄罗斯莫斯科。 她是一个研究 纽约大学药理学系助理教授 大学医学中心。 长期的职业目标将是获得 了解阿片肽及其参与调节 生理功能。 纽约大学医学中心和R. L. 德维的实验室提供了必要的智力环境， 一个强大的研究计划的发展。 此外，L. Devi 将建议和指导候选人成为一名独立的科学家， 致力于富有成效的生物医学研究事业。 候选人的职业目标是研究阿片类药物的作用 系统在小鼠模型中用于肥胖脂肪/脂肪。 这个小鼠模型是 缺乏羧肽酶E，一种参与成熟的酶， 阿片肽和调节分泌途径分选受体。 在肥胖/肥胖小鼠的大脑中， 加工阿片肽和大量增加的水平COOH- 末端延伸肽，含高分子量强啡肽 肽和未加工的强啡肽原。 在这份资助申请中， IR-强啡肽和IR-脑啡肽的区域分布， 成年和发育中的肥胖/肥胖小鼠大脑中的mRNA水平将被 具体目标（1）。 这些研究将提供以下信息： 水平的差异分布和发展变化 阿片肽 强啡肽水平变化的影响 阿片受体系统上的肽将在成人中进行检查， 发育肥胖/肥胖小鼠（具体目标2）。 受体总数和 激动剂刺激的GTP [g-35 S]结合将通过 放射自显影和腺苷酸环化酶活性将用于 微米、δ和κ阿片受体的功能定量。 这些研究将有助于了解阿片受体系统 适应不完全的肽加工。 假设受损的 肥胖/肥胖小鼠中的强啡肽原加工是不正确的 将评估以不受调节的方式进行的分选和分泌 （具体目标3）。 这些研究将提供有关CPE如何 闭塞导致前强啡肽加工和释放不完全 异常肥胖/肥胖和瘦同窝小鼠的反应性 到微米，δ和κ激动剂和拮抗剂， 将检查进食行为（具体目标4）。激动剂或 拮抗剂将急性给药， 将确定注射后1小时。 剂量反应 将生成曲线。 这些研究将提供以下信息： 参与肥胖/肥胖小鼠喂养的阿片受体类型， 肥胖症的发展。