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
基本信息
- 批准号:8539520
- 负责人:
- 金额:$ 15.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:16p11.222q11.29p24.1AcuteAffectAgonistBehavioral ParadigmBiologicalBiological ProcessBiologyBipolar DisorderBrainCellsChromosomesChronicClinicalCollectionComplexDNA Sequence RearrangementDiseaseDoseDouble-Blind MethodEP300 geneEpilepsyExtended FamilyFamilyFamily memberFunctional Magnetic Resonance ImagingFunctional disorderGenesGeneticGlutamatesGlutamineGlycineGlycine decarboxylaseHomeostasisIndividualInterventionLinkMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMeasuresMediatingMental RetardationMental disordersMetabolismMolecularMood DisordersMusMutationN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeurobiologyNeurocognitiveNeurodevelopmental DisorderNeurogliaOdds RatioOralPathway interactionsPatientsPharmacodynamicsPlacebo ControlPlacebosPlasmaProceduresPropertyProtonsPsychotic DisordersPsychotropic DrugsRegimenRiskRisk FactorsScanningSchizophreniaSymptomsTimeTreatment EfficacyVariantVisualVisual evoked cortical potentialautism spectrum disorderbasebrain pathwayclinical effectcognitive functiondouble-blind placebo controlled trialduplicate genesexpectationextracellularfollow-upgamma-Aminobutyric Acidgenetic risk factorgenetic variantimprovedmagnocellularmicrodeletionmutation carrierneurochemistryneuropsychiatryneurotransmissionopen labeloverexpressionreceptor functionresponsetransmission processvisual processvisual processing
项目摘要
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):最近的研究结果表明,复杂精神疾病的遗传变异的一个显着比例可以解释为一个单独的罕见的,高度外显的遗传变异的集合。这些拷贝数变异(CNV)中的每一种都可能是疾病的风险因素,并且许多是非复发性和散发性的。最佳地,特定突变的鉴定将导致针对突变的潜在生物学定制的个性化治疗干预。我们已经确定了一个复杂的结构重排在9p24.1分离与精神病在一个家庭。重排区域中的一个基因,甘氨酸脱羧酶(GLDC),参与神经胶质细胞中甘氨酸的降解,并在突变携带者中是三重的。甘氨酸是N-甲基-D-天冬氨酸受体(NMDAR)的共激动剂。预期GLDC三倍体的携带者具有低水平的脑甘氨酸,导致NMDAR介导的功能减退,其强烈地涉及精神分裂症的病理生理学。这种突变的携带者是受益于甘氨酸增强其精神药物方案的强有力的候选者。这项R21申请的一个目的是在这种突变的携带者中进行原理验证的双盲安慰剂对照甘氨酸增强试验,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的突变携带者和非携带者进行有针对性的神经生物学随访,以表征这种突变的脑结构,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剂量后脑和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通路(大细胞)。在开放标签甘氨酸增加6周后,将对载体重新进行相同的程序(甘氨酸加载扫描除外)。这些结果将显著增强我们对与精神病相关的罕见CNVs的神经生物学及其与疾病病理生理学的相关性的理解。更重要的是,这些结果将首次将病理生理学和医学上可行的治疗干预与潜在的遗传学联系起来,对其他患有神经精神疾病的患者具有潜在的益处,这些患者在同一基因或其他基因/途径中具有突变,这些基因/途径受到相同或相关异常生物过程的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DEBORAH L LEVY其他文献
DEBORAH L LEVY的其他文献
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{{ truncateString('DEBORAH L LEVY', 18)}}的其他基金
Targeting a Genetic Mutation in Glycine Metabolism with D-Cycloserine
用 D-环丝氨酸靶向甘氨酸代谢中的基因突变
- 批准号:
8805873 - 财政年份:2014
- 资助金额:
$ 15.17万 - 项目类别:
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:
8443634 - 财政年份:2012
- 资助金额:
$ 15.17万 - 项目类别:
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:
8854200 - 财政年份:2012
- 资助金额:
$ 15.17万 - 项目类别:
PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA
与精神分裂症相关的基因的多效性
- 批准号:
7032078 - 财政年份:2006
- 资助金额:
$ 15.17万 - 项目类别:
PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA
与精神分裂症相关的基因的多效性
- 批准号:
7536095 - 财政年份:2006
- 资助金额:
$ 15.17万 - 项目类别:
PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA
与精神分裂症相关的基因的多效性
- 批准号:
7174618 - 财政年份:2006
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$ 15.17万 - 项目类别:
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$ 15.17万 - 项目类别:
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$ 15.17万 - 项目类别:
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