Characterizing human-specific expression of ZP2 in the cerebellum

表征小脑中 ZP2 的人类特异性表达

基本信息

批准号：
10542433
负责人：
Adriana Cherskov
金额：
$ 5.27万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10542433
关键词：
3-Dimensional Address Adult Affect Affective Affective Symptoms 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 Disparate Distal Electron Microscopy Emotional Environment Exhibits Extracellular Matrix Fertilization Fetal Development Fiber Genes Goals Healthcare Systems Human Impairment In Vitro Knock-out Memory Modeling Molecular Conformation Molecular Target Morphology Motor Movement Disorders Neurobehavioral Manifestations Neurodevelopmental Disorder Neurons Oocytes Organoids Phenotype Physicians Pongidae Pontine structure Primates Protein Secretion Proteins Psychiatric therapeutic procedure Regulation Research Role Scientist Shapes Short-Term Memory Structure Symptoms Synapses Testing Tissue-Specific Gene Expression Tissues Training Work ZP2 Zona Pellucida autism spectrum disorder brain tissue career cognitive function cost disability education planning 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

项目摘要

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.

概括寻找神经精神疾病的新疗法是当务之急，因为这些疾病影响超过五分之一的美国成年人患有此病，每年给美国医疗保健系统造成超过 1800 亿美元的损失。挑战限制对新疗法的追求包括 1) 与使用动物建模更高的相关问题认知行为和 2）不同大脑区域的影响，当受到干扰时，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，本提案将表征基因 ZP2 的表达和缺失相关表型，该基因表现出小脑中的人类特异性表达。小脑最近与协调高级认知功能，其破坏不仅与运动有关，而且与运动有关还伴有认知和情感症状。在一项全面的大脑转录组研究中，塞斯坦实验室检查了人类和灵长类动物之间的差异基因表达，发现 ZP2，一种典型地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在人类小脑中也有独特表达。本提案将调查 ZP2 在颗粒细胞树突上的潜在类似作用，假设 ZP2 锚定在颗粒细胞树突上并指导突触发生和发育过程中苔藓纤维的相互作用。为此，本提案包括利用出生后、手术后和死后的人类脑组织和分化的人类脑组织诱导多能干细胞作为模型系统来定位 ZP2 表达，确定 ZP2 结合合作伙伴，并确定 ZP2 是否在机制上参与突触的发育小脑颗粒细胞和苔藓纤维之间。这项工作有可能揭示人类可能独有的突触发育机制和潜在的分子靶点用于定位于小脑的人类特定认知功能。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。