Bidirectional control of Chd2 haploinsufficiency

摘要 在绘制癫痫和其他神经发育的遗传基础图方面取得了重大进展 精神障碍(NDDS)。在许多情况下，已经确定了候选基因突变，但没有可靠的 了解导致这种特殊疾病的神经原因。染色质编码基因的突变 调节剂通常在人类NDD中被发现，并伴有智力残疾、自闭症和/或癫痫。 发生在同一个人身上的。我们最近的工作表明，具有生殖系杂合突变的小鼠 CHD2表现出跨越基因组、解剖、电生理和行为领域的病理变化。 在这里，我们建议研究在发育中或成人大脑中双向控制CHD2的剂量。我们的方法 涉及复杂的细胞、分子、药理学和电生理学的组合 条件性CHD2+/-小鼠和人源性神经元的研究方法。如果成功，我们的结果将提供 关于染色质调节剂在推动新城疫相关病理中的作用的重要新信息 并将为药物增加的治疗潜力提供关键的概念验证 CHD2的表达，可迅速转化为CHD2单倍体功能不全的新靶向治疗。

ABSTRACT Major advances have been made in mapping the genetic basis of epilepsy and other neurodevelopmental disorders (NDDs). In many cases, a candidate gene mutation has been identified, but there is no robust understanding of the neuronal causes for the particular disorder. Mutations in genes encoding chromatin regulators are commonly identified in human NDDs, with intellectual disability, autism and/or epilepsy often co- occurring in the same individual. Our recent work showed that mice with germline heterozygous mutations in Chd2 exhibit pathological changes across genomic, anatomical, electrophysiological and behavioral domains. Here, we propose studies to bidirectionally control Chd2 dosage in the developing or adult brain. Our approach involves a combination of sophisticated cellular, molecular, pharmacologic and electrophysiological approaches in conditional Chd2+/- mice and human-derived neurons. If successful, our results will provide important new information about the effects of chromatin regulators in driving NDD-associated pathologies in vivo and would provide critical proof-of-concept for the therapeutic potential of pharmacologically increasing Chd2 expression that could be rapidly translated into a new targeted therapy for Chd2 haploinsufficiency.