PROTRH GENE TRANSCRIPTION AND BIOSYNTHESIS BY LEPTIN

PROTRH 基因转录和瘦素生物合成

• 批准号: 6637162
• 负责人: EDUARDO A. NILLNI
• 金额: $ 30.71万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637162
• 关键词: carboxypeptidase; gene expression; genetic regulation; genetic transcription; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary axis; hypothalamus; laboratory rat; leptin; melanocyte stimulating hormone; messenger RNA; neurons; peptide hormone biosynthesis; pituitary thyroid axis; polymerase chain reaction; posttranslational modifications; prohormone convertase; secretion; starvation; thyroid hormones; thyrotropin releasing hormone; tissue /cell culture

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.

作为对饥饿的适应性反应，下丘脑-垂体-甲状腺轴下调。 这至少部分是由下丘脑中proTRH mRNA表达的抑制引起的，这可以被瘦素逆转。 有资料表明，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，所述AC神经元是瘦素反应性的并且投射到PVN，其中产生proTRH的促垂体神经元位于PVN。 然而，我们实验室最近进行的一项新的工作强烈表明，TRH神经元也可能直接受瘦素调节，而没有中间途径。因此，在这个建议中，我们将确定参与行动的瘦素在促甲状腺激素释放激素（TRH）神经元的proTRH生命周期的分子事件。作为模型系统，我们将利用我们建立的表达高水平内源性促甲状腺激素释放激素原和瘦素受体的下丘脑神经元的原代培养物。 某些方面将通过体内研究得到证实。