Role of ARX mutations in marmoset brain organoids

项目摘要/摘要 神经精神障碍是导致残疾的主要原因，影响了近19%的美国人口。 进入临床试验的神经精神药物只有9%进入市场，这是成功率最低的药物之一。 在所有治疗领域的比率。啮齿动物和人类神经生物学的根本区别 已经被提议解释在开发有效的治疗策略方面的翻译失败 减轻神经或神经退行性疾病或紊乱。啮齿动物的行为分析也是不同的 有效地预测临床上有效的神经精神药物。非人灵长类(NHP)被认为是 一种有价值的、具有临床意义的替代方案，可以跨越啮齿动物和人类之间在发育过程中的差距 旨在促进大脑健康的疗法。在NHP中，常见的绒猴或Callithrix Jacchus(CJ) 由于其体积小、寿命短、每年生产多个后代，因此提供了一个高度易处理的选项 以及对人类神经解剖学的准确概括。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基因改造的研究，因此仍处于初级阶段， 尤其是那些需要概括大脑健康复杂方面的内容。为了解决这一迫切需要，我们将 靠近NIH指定的两个Marmoset繁育群体之一(U24 MH123422，资助 根据RFA-MH-20-145)在西南国家灵长类研究中心维护)和领先的专业知识 在大脑健康和疾病方面，特别是癫痫的神经遗传学方面。在这份多样性补充资料中， 我们将执行父U01应用程序的目标3中概述的实验，即评估 ARX突变对绒猴皮质神经元发育和迁移的影响。这一目标旨在推进 绒猴模型在脑研究中的应用--基于PSC来源的脑器官和 ARX突变对神经系统影响的专门知识。

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.