IGFBP3 colocalizes with and regulates hypocretin (orexin).
IGFBP3 colocalizes with and regulates hypocretin (orexin).
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IGFBP3 与下丘脑分泌素（食欲素）共定位并对其进行调节。
DOI：
10.1371/journal.pone.0004254
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Mignot E
中科院分区：
文献类型：
--
作者：
Honda M;Eriksson KS;Zhang S;Tanaka S;Lin L;Salehi A;Hesla PE;Maehlen J;Gaus SE;Yanagisawa M;Sakurai T;Taheri S;Tsuchiya K;Honda Y;Mignot E
睡眠障碍发作性睡病是由产生下丘脑分泌素（食欲素）神经肽的神经元大量减少引起的。基于与 HLA 的紧密相关性，发作性睡病被认为是由自身免疫攻击引起的，但下丘脑分泌素细胞丢失的原因仍不清楚。我们在下丘脑中进行了基因表达谱分析，以识别发作性睡病中失调的新基因，因为这些基因可能是自身免疫攻击的目标或调节下丘脑分泌素基因表达。我们使用微阵列来比较（1）发作性睡病患者与对照死后人脑以及（2）缺乏下丘脑分泌素神经元的转基因小鼠与野生型小鼠的下丘脑后部的转录组。下丘脑分泌素是人类发作性睡病大脑中下调幅度最大的基因。在许多其他候选蛋白中，只有一种胰岛素样生长因子结合蛋白 3 (IGFBP3) 在人和小鼠模型中下调，并在下丘脑分泌素神经元中共表达。功能分析表明，在过度表达人 IGFBP3 的转基因小鼠中，下丘脑泌素信使 RNA 和肽含量降低，睡眠增加，这种效应可能是通过在存在过量 IGFBP3 的情况下下丘脑泌素启动子活性降低介导的。尽管我们在人类发作性睡病中没有发现 IGFBP3 自身抗体，也没有发现与 IGFBP3 多态性的遗传关联，但我们发现已知会增加血清 IGFBP3 水平的 IGFBP3 多态性与正常个体中脑脊液下丘脑分泌素-1 的降低相关。对发作性睡病和发作性睡病模型小鼠大脑中的转录组的比较揭示了一种新的失调基因，该基因共定位于下丘脑分泌素细胞中。功能分析表明，所鉴定的 IGFBP3 是下丘脑分泌素细胞生理学的新调节因子，可能不仅参与发作性睡病的病理生理学，而且还参与正常个体的睡眠调节，尤其是在青春期。需要进一步的研究来解决 IGFBP3 过度表达可能引发下丘脑分泌素细胞死亡并导致发作性睡病的假设。
The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals. Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.
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影响因子：
64.5
作者：
Lin, L;Faraco, J;Mignot, E
通讯作者：
Mignot, E
影响因子：
12.3
作者：
Franz, Henriette;Ullmann, Claudia;Khaitovich, Philipp
通讯作者：
Khaitovich, Philipp
影响因子：
4.8
作者：
Modric, T;Silha, JV;Murphy, LJ
通讯作者：
Murphy, LJ
DOI：
10.1196/annals.1308.032
发表时间：
2004-01-01
期刊：
ADOLESCENT BRAIN DEVELOPMENT: VULNERABILITIES AND OPPORTUNITIES
影响因子：
--
作者：
Carskadon, MA;Acebo, C;Jenni, OG
通讯作者：
Jenni, OG
DOI：
10.1084/jem.190.7.895
发表时间：
1999-10-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Coyle AJ;Lloyd C;Tian J;Nguyen T;Erikkson C;Wang L;Ottoson P;Persson P;Delaney T;Lehar S;Lin S;Poisson L;Meisel C;Kamradt T;Bjerke T;Levinson D;Gutierrez-Ramos JC
通讯作者：
Gutierrez-Ramos JC