新しいモデルは、自閉症や統合失調症などの複雑な精神障害の検出に役立ちます

マウントシナイ幹細胞モデルは、いくつかの精神障害の背後にある複雑な生物学に光を当てることができるかもしれません。

人間のニューロンの病気のリスクの変化をマッピングするために、 マウントサイナイ医科大学 独自の幹細胞モデルを使用しました。 この作品は、自閉症や統合失調症などの神経精神病の根底にある生物学的メカニズムに光を当てるのに役立つかもしれません。

ナンヤン博士、神経科学の助教授。 クレジット：Mount Sinai Health System

最近CellReportsに発表されたこのグループの実験室ラベル付き細胞モデルは、精神障害のさまざまなリスク対立遺伝子（リスクを与える一般的な遺伝的変異）を特徴付けるゲノムワイド関連解析（GWAS）を含む疾患メカニズムの将来の研究者の理解を促進するために作成されました。 この研究は、患者が症状を発症する何年も前に精神的な問題を検出するためのより良い診断方法を開発するのに役立つ可能性があります。

この研究は、精神障害の遺伝率に関連している可能性のある、ヒトニューロンのシス調節エレメントの特定に焦点を当てています。 エンハンサーとプロモーターを含むシス調節エレメントは非コードです[{” attribute=””>DNA regions that control the expression of genes and are essential parts of the genetic regulatory network. A considerable enrichment of common variants in the cis-regulatory elements, including those linked to bipolar disorder, schizophrenia, and autism spectrum disorder, has been found in previous genetic investigations.

“While common risk variants can shed light on the underlying molecular mechanism, identifying causal variants remains challenging for scientists,” says Nan Yang, Ph.D., Assistant Professor of Neuroscience at the Icahn School of Medicine of Mount Sinai, and senior author of the study. “That’s because cis-regulatory elements, particularly the enhancers, vary across cell types and activity states. Typically, researchers can only use postmortem brain samples where the neurons are no longer active. As a result, they are likely to miss enhancers that only respond to stimulation. Our approach is to map cis-regulatory elements in human neurons derived from pluripotent stem cells. That allows us to replicate neurons in the human brain that can be affected by different types of neuropsychiatric disease, and conduct mechanistic studies of human genetic variants that are inaccessible from other types of human samples.”

In recent years, GWAS have identified hundreds of gene regions associated with psychiatric disease, though understanding disease pathophysiology has been elusive. The functional genomics approach Dr. Yang and her team developed uses stem cell models that can help resolve the impact of patient-specific variants across cell types, genetic backgrounds, and environmental conditions. This unique approach effectively lays a foundation to translate risk variants to genes, genes to pathways, and pathways to circuits that reveal the synergistic relationship between disease risk factors within and between the cell types in the brain.

“Our research attempts to decode and transfer highly complex genetic insights into medically actionable information,” says Dr. Yang, who is a member of the Black Family Stem Cell Institute, The Friedman Brain Institute, and The Ronald M. Loeb Center for Alzheimer’s Disease within the Mount Sinai Health System. “That means improving our diagnostic capabilities, predicting clinical trajectories, and identifying presymptomatic points of therapeutic intervention for psychiatric disorders.”

By characterizing cell-type specific and activity-regulated gene expression patterns in human cell-derived neurons, Dr. Yang believes her team’s study can greatly benefit the research community. “Our data can guide choosing relevant cell types of experimental conditions to further elucidate molecular mechanisms of disease across the genome,” she points out. “And that could lead to the development of biomarkers that might detect neuropsychiatric disorders years before they manifest themselves in patients, while there is still time to delay or possibly prevent them.”

Reference: “Mapping cis-regulatory elements in human neurons links psychiatric disease heritability and activity-regulated transcriptional programs” by Carlos Sanchez-Priego, Ruiqi Hu, Linda L. Boshans, Matthew Lalli, Justyna A. Janas, Sarah E. Williams, Zhiqiang Dong and Nan Yang, 31 May 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.110877