Mayo K E, Miller T L, DeAlmeida V, Zheng J, Godfrey P A
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208, USA.
Ann N Y Acad Sci. 1996 Dec 26;805:184-203. doi: 10.1111/j.1749-6632.1996.tb17483.x.
We now summarize key issues that we have investigated and highlight additional areas that need to be addressed. We are interested in two basic aspects of the GHRH pathway, those occurring in the brain, involving the synthesis of GHRH, and those occurring in the pituitary, involving signaling by GHRH. We have a long-term interest in the activity and regulation of the hypothalamic neurosecretory cells that synthesize GHRH. With respect to human disease, it is interesting that, despite the primal role played by GHRH in growth-hormone secretion, no mutations in the GHRH gene have yet been identified in association with growth disorders. Focusing on the downstream signaling components of the GHRH pathway, we now know quite a lot about the structure of the GHRH receptor and about some aspects of the signal transduction pathways that mediate the actions of GHRH. With respect to human disease, we have found that in an animal model, the little mouse, a mutation of the GHRH receptor results in growth-hormone deficiency and a dwarf phenotype, and there are ongoing attempts in several laboratories to try to identify similar inactivating mutations in the GHRH receptor in patients with isolated growth-hormone deficiency. Conversely, there is also substantial interest in whether activating mutations in this receptor might be identified in patients with growth-hormone-secreting pituitary tumors. We are also interested in whether there are additional receptors that might mediate some of the extrapituitary actions of GHRH. Finally, a major direction we are taking in the laboratory at the present time is toward understanding the developmental, hormonal, and tissue-specific regulation of the GHRH receptor gene.
我们现在总结已研究的关键问题，并强调需要解决的其他领域。我们关注生长激素释放激素（GHRH）通路的两个基本方面，一个是在大脑中发生的，涉及GHRH的合成，另一个是在垂体中发生的，涉及GHRH的信号传导。我们长期关注合成GHRH的下丘脑神经分泌细胞的活性和调节。关于人类疾病，有趣的是，尽管GHRH在生长激素分泌中起主要作用，但尚未发现GHRH基因的突变与生长障碍有关。聚焦于GHRH通路的下游信号成分，我们现在对GHRH受体的结构以及介导GHRH作用的信号转导通路的一些方面已经有了相当多的了解。关于人类疾病，我们发现在一种动物模型——矮小症小鼠中，GHRH受体的突变导致生长激素缺乏和侏儒表型，并且几个实验室正在进行尝试，试图在孤立性生长激素缺乏患者中鉴定GHRH受体的类似失活突变。相反，对于在分泌生长激素的垂体瘤患者中是否可能鉴定出该受体的激活突变也有很大兴趣。我们还对是否存在其他可能介导GHRH一些垂体外作用的受体感兴趣。最后，我们目前在实验室中研究的一个主要方向是了解GHRH受体基因的发育、激素和组织特异性调节。
