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：（改编自申请人的摘要）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 应激反应。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 被认为充当 神经递质介导与压力相关的行为、自主神经和 免疫反应。 CRH 的作用由两类 CRH 介导 受体并受 CRH 结合蛋白调节。几年前，一个新的 Vaughan 及其同事鉴定出了哺乳动物 CRH 样配体。这40 氨基酸神经肽，称为尿皮质素，与 CRH 43% 相同， 与其两种受体结合，但与 CRHR2 的亲和力更高。因为 CRH 和尿皮质素可以结合并激活 CRH 受体（静脉注射或静脉注射） 给予尿皮质素会产生非常相似的生理反应 那些用CRH观察到的。由于尿皮质素与 CRH 受体共定位 的位点数量，研究者假设尿皮质素介导或 调节一些以前认为是介导的生理效应 由CRH。拟议的工作将专门研究其体内作用 中枢神经系统和垂体中的尿皮质素。根据生理实验和 根据神经解剖学数据，研究者假设尿皮质素在 大脑调节进食和饮水行为、焦虑行为和 自主功能。 此外，尿皮质素似乎可能在前部以旁分泌方式起作用。 垂体调节基础或 CRH 介导的 ACTH 分泌。为了测试这些 假设，研究者将进一步表征 成年小鼠中枢神经系统和垂体中的尿皮质素 mRNA 在基础和改变下 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 RNAase 保护测定。第二， 她将创造一种可诱导的大脑特异性尿皮质素敲除小鼠 描述由于缺乏而导致的生理和行为变化 尿皮质素在中枢神经系统中的表达。三、原代垂体前叶培养 将用于测试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 ACTH。 最后，研究人员将检查负责的分子机制 培养细胞和转染中尿皮质素表达的调节 化验。这些研究将有助于更准确地确定 尿皮质素在中枢神经系统和垂体中的生理作用，并区分 它的角色与 CRH 的角色不同。由于 CRH 活性失调被认为是 对于重度抑郁症、焦虑症和厌食症很重要，更清晰的 了解尿皮质素在中枢神经系统和垂体部位的作用可能是 对于我们理解这些人类疾病的病理生理学很重要 州。