Characterizing human-specific expression of ZP2 in the cerebellum

总结 寻找新的治疗神经精神疾病的方法是一个优先事项，因为这些疾病的影响超过 五分之一的美国成年人，每年花费美国医疗保健系统超过1800亿美元。挑战 限制追求新的治疗方法包括：1）与使用动物来模拟更高的 认知行为和2）不同的大脑区域的含义，当被破坏时，表现在 运动、情感和认知领域的不同症状。为了解决这些问题，本提案 将描述ZP2基因的表达和缺失相关表型， 在小脑中的人类特异性表达。小脑最近被认为与 协调更高的认知功能，它的中断不仅与运动有关， 也有认知和情感症状在一项对大脑的综合转录组学研究中， 通过研究人类和灵长类动物之间的差异基因表达，塞斯坦实验室发现， ZP2是一种典型的参与稳定细胞外基质和防止多精受精的蛋白质， 哺乳动物卵母细胞也在人小脑中独特表达。该提案将调查 ZP2在颗粒细胞树突上的潜在类似作用，假设ZP2锚定在树突上， 并在突触发生和发育期间指导苔藓纤维相互作用。为此，该提案 包括利用出生后、手术后和死后人脑组织和分化的人脑 诱导多能干细胞作为模型系统定位ZP2表达，确定ZP2结合 合作伙伴，并确定是否ZP2是机械牵连的发展突触 小脑颗粒细胞和苔藓纤维之间的联系这项工作有可能揭示 突触发育机制可能是人类独有的，也是潜在的分子靶点。 人类特有的认知功能定位于小脑。此应用程序还包括一个 培训计划，将准备申请人的职业生涯调查神经发育障碍， 临床科学家

SUMMARY Finding new treatments for neuropsychiatric disorders is a priority, as these disorders affect over 1 in 5 US adults and cost the US health care system over 180 billion dollars annually. Challenges limiting the pursuit of new treatments include 1) issues associated with using animals to model higher cognitive behaviors and 2) the implication of disparate brain regions that, when disrupted, manifest in diverse symptoms in motor, affective, and cognitive domains. To address these issues, this proposal will characterize the expression and deletion-associated phenotypes of a gene, ZP2, that exhibits human-specific expression in the cerebellum. The cerebellum has recently been implicated in coordinating higher cognitive functions, and its disruption has been associated not only with motor but also with cognitive and affective symptoms. In a comprehensive transcriptomic study of the brain, examining differential gene expression between humans and primates, the Sestan lab discovered that ZP2, a protein canonically involved in stabilizing the extracellular matrix and preventing polyspermy at the mammalian oocyte, is also uniquely expressed in human cerebellum. This proposal will investigate a potential analogous role of ZP2 at the granule cell dendrite, where it is hypothesized that ZP2 anchors and guides mossy fiber interactions during synaptogenesis and development. To do so, this proposal includes utilizing postnatal post-surgical and post-mortem human brain tissue and differentiated human induced pluripotent stem cells as a model system to localize ZP2 expression, determine ZP2 binding partners, and determine whether ZP2 is mechanistically implicated in the development of synapses between cerebellar granule cells and mossy fibers. This work has the potential to shed light on mechanisms of synaptic development that may be unique to humans and a potential molecular target for human-specific cognitive functioning localized to the cerebellum. This application also includes a training plan that will prepare the applicant for a career investigating neurodevelopmental disorders as a clinician-scientist.