ROLE OF UROCORTIN IN MAMMALIAN BRAIN AND PITUITARY

尿皮质素在哺乳动物大脑和垂体中的作用

• 批准号: 6498183
• 负责人: AUDREY F. SEASHOLTZ
• 金额: $ 24.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498183
• 关键词: adrenalectomy; adrenocorticotropic hormone; anxiety; autonomic nervous system; brain; corticosterone; corticotropin releasing factor; dexamethasone; eating; fasting; genetic transcription; hormone regulation /control mechanism; laboratory mouse; laboratory rat; messenger RNA; pituitary gland; polymerase chain reaction; psychological stressor

DESCRIPTION: (Adapted from the applicant's abstract) Corticotropin-releasing hormone (CRH) is recognized as the key hypothalamic regulator of the mammalian stress response. Within the hypothalamic-pituitary-adrenal axis (HPA), hypothalamic CRH is the principal hormone controlling pituitary ACTH secretion. At other sites in the central nervous system, CRH is thought to act as a neurotransmitter to mediate stress-related behavioral, autonomic, and immunological responses. The effects of CRH are mediated by two classes of CRH receptors and are modulated by a CRH-binding protein. Several years ago, a new mammalian CRH-like ligand was identified by Vaughan and colleagues. This 40 amino acid neuropeptide, called urocortin, is 43 percent identical to CRH and binds to both of its receptors, albeit with a higher affinity to CRHR2. Because CRH and urocortin can bind to and activate both CRH receptors, iv or icv administration of urocortin results in very similar physiological responses to those observed with CRH. Since urocortin is colocalized with CRH receptors in a number of sites, the investigator hypothesize that urocortin mediates or modulates some of the physiological effects previously thought to be mediated by CRH. The proposed work will specifically examine the in vivo role of urocortin in the CNS and pituitary. Based upon physiological experiments and neuroanatomical data, the investigator hypothesizes that urocortin acts in the brain to modulate feeding and drinking behavior, anxiogenic behavior, and autonomic function. Also it appears that urocortin might act in a paracrine fashion in the anterior pituitary to modulate basal or CRH-mediated ACTH secretion. To test these hypotheses, the investigator will further characterize the expression of urocortin mRNA in the adult mouse CNS and pituitary under basal and altered physiological states (stress, altered glucocorticoid status, food or water deprivation) using in situ hybridization and RNAase protection assays. Second, she will create an inducible brain-specific urocortin knockout mouse and characterize the physiological and behavioral changes resulting from the lack of urocortin expression in the CNS. Third, primary anterior pituitary cultures will be used to test the role of pituitary urocortin in basal and stimulated ACTH secretion from corticotropes. Finally, the investigator will examine the molecular mechanisms responsible for regulation of urocortin expression in cultured cells and in transfection assays. These studies will allow a more accurate determination of the physiological role(s) of urocortin in CNS and pituitary, and to differentiate its roles from those of CRH. As dysregulation of CRH activity is thought to be important in major depression, anxiety disorders, and anorexia, a clearer understanding of the role(s) of urocortin in CNS and pituitary sites may be important to our understanding of the pathophysiology of these human disease states.

描述：(改编自申请者摘要)促肾上腺皮质激素释放 激素(CRH)被认为是哺乳动物下丘脑的关键调节因子。 压力反应。在下丘脑-垂体-肾上腺轴(HPA)内， 下丘脑CRH是控制垂体ACTH分泌的主要激素。 在中枢神经系统的其他部位，CRH被认为是一种 神经递质调节应激相关的行为、自主神经和 免疫反应。CRH的作用由两类CRH介导 受体，并由CRH结合蛋白调节。几年前，一个新的 哺乳动物的CRH样配体是由Vaughan和他的同事发现的。这40岁 氨基酸神经肽，称为尿皮质素，与CRH和CRH有43%的同源性 与两种受体结合，但与CRHR2的亲和力较高。因为 CRH和urocortin可以结合并激活两种CRH受体，iv或icv 给药后，尿皮质激素的生理反应非常相似 CRH观察到的。由于Urocortin与CRH受体共同定位于 的数量，研究人员假设尿皮质激素调节或 调节一些以前被认为是中介的生理效应 由CRH提供。这项拟议的工作将专门研究在体内的作用 中枢神经和脑下垂体中的尿皮质素。基于生理实验和 神经解剖学数据，研究人员假设Urocortin在 大脑调节进食和饮酒行为，焦虑行为，以及 自主神经功能。 此外，可能在大脑前叶中起旁分泌作用。 调节基础或CRH介导的ACTH分泌。为了测试这些 假设，调查者将进一步描述 成年小鼠中枢神经系统和垂体中urocortin mRNA的基础和变化 生理状态(压力、糖皮质激素状态改变、食物或水 剥夺)使用原位杂交和RNA酶保护分析。第二, 她将创造一种可诱导的脑特异性urocortin基因敲除小鼠，并 描述由于缺乏而导致的生理和行为变化 Urocortin在中枢神经系统的表达。第三，原代垂体前叶培养 将用于测试脑下垂体尿皮质素在基础和刺激中的作用 促肾上腺皮质激素分泌。 最后，研究人员将检查负责的分子机制 Urocortin在培养细胞和转染体中的表达调控 化验。这些研究将使我们能够更准确地确定 尿皮质激素在中枢和垂体中的生理作用(S)及其分化 它的作用有别于CRH的作用。由于CRH活性的失调被认为是 对严重的抑郁症、焦虑症和厌食症很重要， 对Urocortin在中枢和垂体部位的作用(S)的理解可能是 对我们理解这些人类疾病的病理生理学很重要 各州。