Characterizing human-specific expression of ZP2 in the cerebellum

表征小脑中 ZP2 的人类特异性表达

• 批准号: 10316165
• 负责人: Adriana Cherskov
• 金额: $ 3.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316165
• 关键词: 3-Dimensional; Address; Adult; Affect; Affective; Affective Symptoms; Alpha Granule; Animal Model; Animals; Ataxia; Attention; Autopsy; Axon; Behavior; Binding; Biological Models; Biopsy; Brain; Brain region; CRISPR/Cas technology; Cells; Cerebellum; Coculture Techniques; Cognition; Cognitive; Data; Decision Making; Dendrites; Development; Developmental Process; Disease; Distal; Electron Microscopy; Emotional; Environment; Exhibits; Extracellular Matrix; Fertilization; Fetal Development; Fiber; Genes; Goals; Healthcare Systems; Human; Impairment; In Vitro; Knock-out; Lead; Light; Memory; Modeling; Molecular Conformation; Molecular Target; Morphology; Motor; Movement Disorders; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Oocytes; Operative Surgical Procedures; Organoids; Phenotype; Physicians; Pongidae; Pontine structure; Primates; Proteins; Psychiatric therapeutic procedure; Regulation; Research; Role; Scientist; Shapes; Short-Term Memory; Structure; Symptoms; Synapses; Testing; Tissue Differentiation; Tissue-Specific Gene Expression; Tissues; Training; Work; ZP2; Zona Pellucida; autism spectrum disorder; brain tissue; career; cognitive function; cost; disability; effective therapy; egg; fiber cell; granule cell; induced pluripotent stem cell; insight; language impairment; mossy fiber; motor control; neurodevelopment; neuropsychiatric disorder; neuropsychiatry; nonhuman primate; postnatal; prevent; sound; sperm cell; synaptogenesis; transcriptomics

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.

概括 为神经精神疾病寻找新的治疗方法是当务之急，因为这些疾病影响 美国五分之一的成年人和美国医疗保健系统每年超过1800亿美元。挑战 限制对新疗法的追求包括1）与使用动物建模更高相关的问题 认知行为和2）不同大脑区域的含义，当被破坏时， 运动，情感和认知领域的各种症状。为了解决这些问题，该提议 将表征表现出的基因ZP2的表达和缺失相关的表型 小脑中的人类特异性表达。小脑最近与 协调较高的认知功能及其中断不仅与电动机有关 还具有认知和情感症状。在大脑的全面转录组研究中， 检查人类与灵长类动物之间的差异基因表达，塞斯坦实验室发现 ZP2，一种蛋白质，参与稳定细胞外基质并防止多植物的蛋白质 哺乳动物的卵母细胞也在人小脑中唯一表达。该提议将调查 ZP2在颗粒细胞树突中的潜在类似作用，假设ZP2锚定 并指导突触发生和发育过程中的苔藓纤维相互作用。为此，这个建议 包括利用产后外科和验尸后人脑组织，并分化了人类 诱导多能干细胞作为模型系统，用于定位ZP2表达，确定ZP2结合 合作伙伴，并确定ZP2是否在机械上与突触的发展有关 小脑颗粒细胞和苔藓纤维之间。这项工作有可能阐明 可能是人类独有的突触发育机制和潜在的分子靶 对于局限于小脑的人类特异性认知功能。该应用程序还包括一个 培训计划将使申请人为调查神经发育障碍的职业做好准备 临床医生科学家。