PROTRH GENE TRANSCRIPTION AND BIOSYNTHESIS BY LEPTIN

作为对饥饿的适应性反应，下丘脑-垂体-甲状腺轴被下调。这至少在一定程度上是由于下丘脑中突起蛋白mRNA的表达受到抑制，而瘦素可以逆转这种抑制。一些数据表明，瘦素对下丘脑室旁核（PVN） TRH神经元的作用是通过涉及下丘脑弓状核（AC）的间接途径发生的。这可能涉及从AC神经元释放神经肽，如NPY， MSH AgRP，这些神经肽对瘦素有反应，并投射到PVN， PVN是产生prohnh的嗜垂体神经元所在的地方。然而，最近在我们实验室完成的一项新工作强烈表明，TRH神经元也可能直接由瘦素调节，而不需要中间途径。因此，在本提案中，我们将确定瘦素对TRH神经元中突起生命周期的作用所涉及的分子事件。作为一个模型系统，我们将利用我们已经建立的表达高水平内源性肽肽和瘦素受体的下丘脑神经元的原代培养。一些方面将得到体内研究的证实。

As an adaptive response to starvation, the hypothalamic- pituitary-thyroid axis is down-regulated. This is caused, at least in part, by suppression of proTRH mRNA expression in the hypothalamus, which can be reversed by leptin. Some data suggest that the action of leptin on TRH neurons in the paraventricular nucleus (PVN) of the hypothalamus occur through an indirect pathway involving the arcuate nucleus (AC) of the hypothalamus. This may involve release of neuropeptides such as NPY, MSH AgRP from AC neurons that are leptin responsive and that project to the PVN where the hypophysiotropic neurons producing proTRH are located. However, a new line of work done recently in our laboratories strongly suggests that TRH neurons may also be regulated directly by leptin without intermediate pathways. Thus, in this proposal we will identify molecular events involved in the action of leptin on the proTRH life cycle in TRH neurons. As a model system we will utilize our established primary cultures of hypothalamic neurons that express high levels of endogenous proTRH and leptin receptors. Some aspects will be corroborated with in vivo studies.