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: 10468740
• 负责人: Joseph F. Cubells
• 金额: $ 64.84万
• 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/10468740
• 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; Gene Expression Profile; Generations; Genes; Genetic; Genetic Diseases; Glutamates; Heart Abnormalities; Heritability; Human; Immune; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Knowledge; Lead; Light; Link; Live Birth; Measures; Molecular; Neurobehavioral Manifestations; Neuronal Dysfunction; Neurons; Patients; Persons; Phenotype; Physiological; Pluripotent Stem Cells; Population; Property; Psychophysiology; Psychoses; Reflex action; Research; 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; schizophrenia risk

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 在这个修改后的建议中，我们计划研究的生理和突触特性的 多能干细胞（iPSC）衍生的神经元，以及精神分裂症（SCZ）相关的神经元。 生理表型，收集自22 q11缺失综合征（22 q11 DS）患者。 该综合征与精神分裂症风险增加20-30倍有关。20-30%的 22 q11 DS患者在成年早期发生SCZ。声音惊吓反应（ASR） 一种进化上保守的反射，与健康对照组相比，SCZ中的反射方面有所不同。 基于表型，先前对SCZ高风险非22 q11 DS个体的研究 特性（即，有前驱症状的人）表明，ASR的潜伏期预测 转换为SCZ。失配负波（MMN）是一种诱发电位， “古怪的”声刺激嵌入在一系列重复的声刺激中。受损 对古怪刺激的增强反应的产生是复制良好的MMN 在SCZ中观察到异常。我们建议的工作将研究ASR措施和MMN在老年人 22 q11 DS的青少年和年轻成人（和健康对照）来检验假设， ASR和/或MMN的潜伏期将预测前驱症状的严重程度， 转换为SCZ，在这个基因定义的高风险群体中。同时，我们将研究 与来自22 q11 DS的iPSC衍生神经元中的ASR和MMN相关的潜在细胞机制 患者在ASR中表现出极端的惊吓潜伏期。我们假设这样做 将确定22 q11表型影响的潜在细胞机制， 删除（包括SCZ风险升高）。因此，这项研究将揭示基因是如何 机制改变与观察到的临床和生理差异相关的细胞特性 在SCZ和SCZ前驱症状。