ROLE OF UROCORTIN IN MAMMALIAN BRAIN AND PITUITARY

描述：（改编自申请人摘要）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被认为是作为一个神经系统的一部分。 神经递质介导压力相关的行为，自主， 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CRH样配体由Vaughan及其同事鉴定。这40 氨基酸神经肽，称为尿皮质素，与CRH有43%的相同性， 与其两种受体结合，尽管与CRHR 2的亲和力更高。因为 CRH和尿皮质素可以结合并激活CRH受体，静脉或icv 尿皮质素的给药导致非常相似的生理反应， 观察CRH。由于尿皮质素与CRH受体共定位在一个细胞内， 研究者假设尿皮质素介导或 调节一些以前被认为是由 关于CRH拟议的工作将具体审查在体内的作用， 中枢神经系统和垂体中的尿皮质素。基于生理实验和 根据神经解剖学数据，研究者假设尿皮质素在神经系统中起作用。 大脑调节进食和饮水行为，焦虑行为， 自主神经功能 此外，尿皮质素似乎可能在前部以旁分泌方式发挥作用 垂体调节基础或CRH介导的ACTH分泌。测试这些 假设，研究者将进一步表征 基础和改变条件下成年小鼠CNS和垂体中的尿皮质素mRNA 生理状态（应激、糖皮质激素状态改变、食物或水 剥夺）。第二、 她将创造一个可诱导的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 中枢神经系统中尿皮质素的表达。第三，原代垂体前叶培养 将被用来测试垂体urocortin的作用，在基础和刺激 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。 培养细胞和转染中尿皮质素表达的调节 测定。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 从CRH的角色。由于CRH活性失调被认为是 在严重抑郁症、焦虑症和厌食症中， 了解尿皮质素在中枢神经系统和垂体部位的作用， 对我们理解这些人类疾病的病理生理学很重要 states.

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.