Psychosis-related Physiological and Neuronal Phenotypes in 22q11 Deletion Syndrome

22q11 缺失综合征中精神病相关的生理和神经表型

• 批准号: 10005473
• 负责人: Joseph F. Cubells
• 金额: $ 70.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005473
• 关键词: 22q11; Acoustics; Adolescent and Young Adult; Affect; Attenuated; Biological; Categories; Cells; Characteristics; Chromosome 22; Chromosome Arm; Clinical; Cognition; DNA; DiGeorge Syndrome; Diagnosis; Disease; Evoked Potentials; Exhibits; Face; Functional disorder; Generations; Genes; Genetic; Genetic Diseases; Genetic Transcription; Glutamates; Heart Abnormalities; Heritability; Human; Immune; Impaired cognition; Impairment; Individual; Knowledge; Lead; Light; Link; Live Birth; Measures; Molecular; Neurobehavioral Manifestations; Neuronal Dysfunction; Neurons; Patients; Phenotype; Physiological; Pluripotent Stem Cells; Population; Property; Psychophysiology; Psychotic Disorders; Reflex action; Research; Risk; Schizophrenia; Severities; Speed; Startle Reaction; Stimulus; Symptoms; Synapses; Synaptic Transmission; Syndrome; T-Lymphocyte; Testing; Time; Training; Work; base; clinical phenotype; cognitive function; effective therapy; emerging adult; follow-up; genetic predictors; glutamatergic signaling; high risk; high risk population; human subject; indexing; induced pluripotent stem cell; interstitial; nerve stem cell; neuropsychiatry; novel; phenotypic biomarker; predicting response; prepulse inhibition; processing speed; psychotic symptoms; relating to nervous system; response

Project Summary In this revised proposal, we plan to examine the physiological and synaptic properties of pluripotent stem cell (iPSC)-derived neurons, as well as schizophrenia (SCZ)-related physiological phenotypes, gathered from patients with 22q11 Deletion Syndrome (22q11DS). The syndrome associates with a 20-30 fold increase in the risk for schizophrenia. 20-30% of patients with 22q11DS develop SCZ by early adulthood. The acoustic startle response (ASR) is an evolutionarily conserved reflex, aspects of which differ in SCZ compared to healthy controls. Prior work on non-22q11DS individuals at high risk for SCZ based on their phenotypic characteristics (i.e., those with prodromal symptoms) suggest that the latency of ASR predicts conversion to SCZ. Mismatch negativity (MMN) is an evoked potential in response to unusual or “oddball” acoustic stimuli imbedded within a train of repetitive acoustic stimuli. Impaired generation of an enhanced response to the oddball stimuli is the well-replicated MMN abnormality seen in SCZ. Our proposed work will examine ASR measures and MMN in older adolescents and young adults with 22q11DS (and healthy controls) to test the hypothesis that latency of the ASR and/or MMN will predict severity of prodromal symptoms, and ultimately conversion to SCZ, in this genetically defined high-risk group. Simultaneously we will study potential cellular mechanisms related to ASR and MMN in iPSC-derived neurons from 22q11DS patients exhibiting extreme values of latency to startle in the ASR. We hypothesize that doing so will identify potential cellular mechanisms underlying the phenotypic impact of the 22q11 deletion (including elevated risk for SCZ). This research will thus shed light on how genetic mechanisms alter cellular properties relevant to clinical and physiological differences observed in SCZ and the SCZ prodrome.

项目摘要 在此修订的建议中，我们计划检查 多能干细胞（IPSC）衍生的神经元以及精神分裂症（SCZ）相关 从患有22q11缺失综合征患者（22q11ds）的患者收集的生理表型。 该综合征与精神分裂症的风险增加了20-30倍。 20-30％ 22q11ds的患者在成年初期发展SCZ。声学惊吓反应（ASR）是 进化保守的反射，与健康对照相比，SCZ的方面有所不同。 基于表型 特征（即患有前驱症状的特征）表明ASR的潜伏期预测 转换为SCZ。不匹配谈判（MMN）是响应异常或 “ ODBALL”声刺激嵌入了重复的声学刺激的火车中。受损 对ODBALL刺激的增强反应是重复的MMN SCZ中看到的异常。我们提出的工作将检查年龄较大的ASR措施和MMN 青少年和具有22q11ds（和健康对照）的年轻人，以检验以下假设 ASR和/或MMN的延迟将预测前驱症状的严重程度，并最终预测 在这个遗传定义的高风险群体中，转换为SCZ。同时我们将学习 来自IPSC衍生的22q11ds的IPSC衍生神经元中与ASR和MMN有关的潜在细胞机制 在ASR中表现出惊人潜伏期的极端价值。我们假设这样做 将确定22q11表型影响的潜在细胞机制 删除（包括SCZ风险升高）。因此，这项研究将阐明遗传 机制改变了与临床和身体差异相关的细胞特性 在SCZ和SCZ前代。