Role of ARX mutations in marmoset brain organoids

项目总结/摘要 神经精神障碍是导致残疾的主要原因，影响近19%的美国人口。 进入临床试验的神经精神药物只有9%到达市场，这是成功率最低的药物之一 在所有治疗领域的应用。啮齿动物和人类神经生物学的根本差异 已经提出在开发有效的治疗策略中解释翻译失败， 减轻神经或神经变性疾病或病症。啮齿类动物行为测定也是非常重要的。 有效预测临床有效的神经精神药物。非人灵长类动物（NHP）被认为是 一个有价值的，临床相关的替代跨越差距之间的啮齿动物和人类的发展， 旨在促进大脑健康的疗法。在NHP中，常见的绒猴或Callithrix jacchus（cj） 提供了一个高度听话的选择，因为它的体积小，寿命短，生产多个后代/年 并准确地概括了人类神经解剖学。然而，绒猴模型的最终效用 由于缺乏有效的工具来促进需要遗传修饰的研究， 特别是那些需要概括大脑健康的复杂方面的人。为了满足这一迫切需要，我们将 联合收割机与两个NIH指定的绒猴繁殖群（U24 MH 123422，资助 根据RFA-MH-20-145）在西南国家灵长类动物研究中心和领先的专业知识 大脑健康和疾病，特别是癫痫的神经遗传学。在这个多样性补充中， 我们将进行U 01申请的目标3中概述的实验，即评估 ARX突变对绒猴皮层神经元发育和迁移的影响这一目标旨在促进 基于PSC衍生的脑类器官的开发，将绒猴模型用于脑研究， 对ARX突变的神经影响的具体知识。

PROJECT SUMMARY/ABSTRACT Neuropsychiatric disorders represent a leading cause of disability, affecting nearly 19% of the US population. Only 9% of neuropsychiatric drugs entering clinical trials reach the market, which is one of the lowest success rates across all therapeutic areas. Fundamental differences between the neurobiology of rodents and humans have been proposed to account for translational failures in development of effective therapeutic strategies to mitigate neurological or neurodegenerative diseases or disorders. Rodent behavioral assays are also variably effective in predicting clinically effective neuropsychiatric drugs. Nonhuman primates (NHPs) are recognized as a valuable, clinically relevant alternative to span the gap between rodents and humans in the development of therapies designed to advance brain health. Among NHPs, the common marmoset or Callithrix jacchus (cj) affords a highly tractable option because of its small size, short lifespan, production of multiple offspring/year and accurate recapitulation of human neuroanatomy. However, the ultimate utility of the marmoset model remains in its infancy due to the paucity of efficient tools to facilitate studies requiring genetic modification, especially those needed to recapitulate complex aspects of brain health. To address this urgent need, we will combine close proximity to one of two NIH-designated Marmoset Breeding Colonies (U24 MH123422, funded under RFA-MH-20-145) maintained at the Southwest National Primate Research Center and leading expertise in brain health and disease in general and the neurogenetics of epilepsy in particular. In this diversity supplement, we will perform the experiments outlined in Aim 3 of the parent U01 application, which is to assess the impact of ARX mutations on marmoset cortical neuron development and migration. This aim is designed to advance the utility of the marmoset model for brain research based on the development of PSC-derived brain organoids and specific knowledge of the neurological impact of ARX mutations.