Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

精神病中甘氨酸代谢突变的神经生物学

• 批准号: 8539520
• 负责人: DEBORAH L LEVY
• 金额: $ 15.17万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539520
• 关键词: 16p11.2; 22q11.2; 9p24.1; Acute; Affect; Agonist; Behavioral Paradigm; Biological; Biological Process; Biology; Bipolar Disorder; Brain; Cells; Chromosomes; Chronic; Clinical; Collection; Complex; DNA Sequence Rearrangement; Disease; Dose; Double-Blind Method; EP300 gene; Epilepsy; Extended Family; Family; Family member; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Glutamates; Glutamine; Glycine; Glycine decarboxylase; Homeostasis; Individual; Intervention; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mental Retardation; Mental disorders; Metabolism; Molecular; Mood Disorders; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurocognitive; Neurodevelopmental Disorder; Neuroglia; Odds Ratio; Oral; Pathway interactions; Patients; Pharmacodynamics; Placebo Control; Placebos; Plasma; Procedures; Property; Protons; Psychotic Disorders; Psychotropic Drugs; Regimen; Risk; Risk Factors; Scanning; Schizophrenia; Symptoms; Time; Treatment Efficacy; Variant; Visual; Visual evoked cortical potential; autism spectrum disorder; base; brain pathway; clinical effect; cognitive function; double-blind placebo controlled trial; duplicate genes; expectation; extracellular; follow-up; gamma-Aminobutyric Acid; genetic risk factor; genetic variant; improved; magnocellular; microdeletion; mutation carrier; neurochemistry; neuropsychiatry; neurotransmission; open label; overexpression; receptor function; response; transmission process; visual process; visual processing

DESCRIPTION (provided by applicant): Recent findings suggest that a significant proportion of the genetic variance in complex psychiatric disorders can be explained by a collection of individually rare, highly penetrant genetic variants. Each of these copy number variants (CNVs) may be a risk factor for disease, and many are non-recurrent and sporadic. Optimally, the identification of specific mutations would result in personalized treatment interventions tailored to the underlying biology of the mutation. We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. The carriers of this mutation are strong candidates to benefit from glycine augmentation of their psychotropic drug regimens. One aim of this R21 application is to carry out a proof-of-principle double-blind placebo-controlled glycin augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function. We also propose to carry out targeted neurobiological follow-up of mutation carriers and non-carriers in the same family in order to characterize the brain structural, functional and neurochemical properties of this mutation. These studies will probe glycine homeostasis using proton magnetic resonance spectroscopy, assess the relationship between brain and plasma glycine levels following an acute oral dose of glycine, and examine brain pathways (magnocellular) implicated in dysregulation of NMDA-mediated neurotransmission. The same procedures (except for the glycine loading scans) will be re-administered to carriers after six weeks of open label glycine augmentation. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will, for the first time, link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.

描述（由申请人提供）：最近的发现表明，复杂的精神疾病中很大一部分遗传差异可以通过集合的单独稀有，高度渗透的遗传变异来解释。这些拷贝数变体（CNV）中的每一个都可能是疾病的危险因素，许多拷贝数是非疾病和零星的。最佳地，对特定突变的识别将导致针对突变的基本生物学量身定制的个性化治疗干预措施。我们已经确定了一个复杂的结构重排在9p24.1，它在一个家庭中与精神病分离。重排区域中的一个基因甘氨酸脱羧酶（GLDC）参与胶质细胞中甘氨酸降解，并在突变载体中进行了一式陈述。甘氨酸是N-甲基-D-天冬氨酸受体（NMDAR）的共同激动剂。 GLDC三分一式认证的载体预计将具有较低的脑甘氨酸，导致NMDAR介导的功能低下，这与精神分裂症的病理生理学密切相关。该突变的载体是强大的候选者，可以从甘氨酸增强其精神药物方案中受益。该R21应用的目的之一是在该突变的携带者中执行原则的双盲安慰剂对照试验，并评估临床症状和神经认知功能的变化。我们还建议对同一家族中突变载体和非载体进行有针对性的神经生物学随访，以表征该突变的大脑结构，功能和神经化学特性。这些研究将使用质子磁共振光谱探测甘氨酸稳态，评估急性口服甘氨酸后大脑与血浆甘氨酸水平之间的关系，并检查与NMDA介导的神经传递失调有关的脑途径（巨细胞）。经过六个星期的开放标签甘氨酸增强，将将相同的程序（除甘氨酸载荷扫描外）被重新管理到携带者。结果将显着增强我们对与精神病相关的罕见CNV及其与疾病病理生理学相关的罕见CNV神经生物学的理解。更重要的是，结果将首次将病理生理学和可操作的治疗干预措施与潜在遗传学联系起来，并可能对其他神经精神病患者或其他基因或其他受相同或相关的异常生物学生物过程影响的神经精神病患者的潜在益处。