Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons.
Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons.
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DOI：
10.1038/tp.2017.37
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发表时间：
2017-03-14
影响因子：
6.8
通讯作者：
Duvvuri V
中科院分区：
文献类型：
--
作者：
Negraes PD;Cugola FR;Herai RH;Trujillo CA;Cristino AS;Chailangkarn T;Muotri AR;Duvvuri V
神经性厌食症（AN）是一种复杂的多因素疾病，主要发生在女性。尽管在精神疾病中死亡率最高，但它仍然缺乏强有力和有效的治疗。像AN这样的疾病最有可能是具有多种遗传贡献的综合征，然而，全基因组研究的力量不足，无法揭示与这种罕见疾病的关联。在这里，我们从患有AN的青春期女性和未受影响的对照中产生了诱导多能干细胞（iPSC）。将这些iPSC分化成神经培养物并进行广泛的转录组分析。在一小群接受治疗的患者中，我们发现了一种新的基因，似乎有助于AN的病理生理学，TACR1（速激肽1受体）。速激肽参与各种生物过程及其与其他神经递质的相互作用表明，一个中断的速激肽系统可能有助于AN症状的新机制。虽然TACR1与精神疾病，特别是焦虑症有关，但我们认为这是它与AN的第一次联系。此外，我们的人类iPSC方法是一个概念验证，即AN可以在体外用完整的人类遗传互补模型建模，并代表了一种新的工具，用于理解疾病背后难以捉摸的分子和细胞机制。
Anorexia nervosa (AN) is a complex and multifactorial disorder occurring predominantly in women. Despite having the highest mortality among psychiatric conditions, it still lacks robust and effective treatment. Disorders such as AN are most likely syndromes with multiple genetic contributions, however, genome-wide studies have been underpowered to reveal associations with this uncommon illness. Here, we generated induced pluripotent stem cells (iPSCs) from adolescent females with AN and unaffected controls. These iPSCs were differentiated into neural cultures and subjected to extensive transcriptome analysis. Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor). The participation of tachykinins in a variety of biological processes and their interactions with other neurotransmitters suggest novel mechanisms for how a disrupted tachykinin system might contribute to AN symptoms. Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN. Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease.