Нов модел помага да се разкрият сложни психиатрични разстройства като аутизъм и шизофрения

Изследването се фокусира върху картографиране на цис-регулаторни компоненти в човешките неврони, които могат да бъдат свързани с наследствеността на психиатричните разстройства.

Модел на стволови клетки от планината Синай може да хвърли светлина върху сложната биология зад определени психиатрични разстройства.

За да картографират вариантите на риска от заболяване в човешките неврони, изследователи от Училището по медицина Икан в планината Синай използва уникален модел на стволови клетки. Тази работа може да помогне да се хвърли светлина върху биологичните механизми зад невропсихиатрични заболявания като аутизъм и шизофрения.

Нан Янг

Нан Янг, д-р, асистент по неврология. Кредит: Здравната система на планината Синай

Клетъчният модел in vitro на групата, който наскоро беше публикуван в списанието Cell Reports, е създаден, за да улесни бъдещите изследователи да разберат механизмите на заболяването, включващи проучвания за асоцииране в целия геном (GWAS), които характеризират различни рискови алели (често срещани генетични варианти, предоставящи риск) за психиатрични разстройства. Това проучване може да помогне за разработването на по-добри диагностични методи за откриване на психични проблеми години преди симптомите на пациента да се проявят.

Изследването се фокусира върху идентифицирането на цис-регулаторни елементи в човешките неврони, които биха могли да бъдат свързани с наследствеността на психиатричните разстройства. Цис-регулаторните елементи, които включват енхансери и промотори, са некодиращи[{” 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 Typically, researchers can only use postmortem brain samples where the neurons are no longer active.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

Alzheimer's disease is a disease that attacks the brain, causing a decline in mental ability that worsens over time. It is the most common form of dementia and accounts for 60 to 80 percent of dementia cases. There is no current cure for Alzheimer's disease, but there are medications that can help ease the symptoms.

” data-gt-translate-attributes=”[{” attribute=””>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

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