Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia

GLS1 抑制在精神分裂症药物治疗中的治疗潜力

基本信息

批准号：
8403407
负责人：
STEPHEN RAYPORT
金额：
$ 34.28万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-06 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403407
关键词：
Acute Address Adult Affect Agonist Alleles Attenuated Behavioral Birth Chronic Clinical Clinical Drug Development Clinical Trials Development Development Plans Early Intervention Embryo Functional Imaging Functional disorder Genetic Glutamates Glutaminase Hippocampus (Brain)Image Knock-out Knockout Mice Knowledge Lead Measures Methylazoxymethanol Acetate Modeling Movement Mus Neurodegenerative Disorders Neurons Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphate Activated Glutaminase Proteins Psychopathology Schizophrenia Stroke Synapses Synaptic Transmission Testing Therapeutic Tissues Translating atypical antipsychotic base clinical application drug candidate drug development endophenotype excitotoxicity high throughput screening inhibitor/antagonist insight intervention effect neurochemistry neurotransmission novel preclinical study presynaptic public health relevance resilience small molecule synaptic inhibition transmission process

项目摘要

DESCRIPTION (provided by applicant): Dysregulated glutamatergic neurotransmission has been strongly implicated in the psychopathology of schizophrenia. Recent studies have highlighted the therapeutic promise of presynaptic reductions in glutamate transmission. We have shown that neurons from glutaminase (GLS1) knockout mice show an activity-dependent presynaptic reduction in glutamatergic synaptic transmission. While GLS1 knockout mice die shortly after birth, GLS1 haploinsufficient mice with one functional GLS1 allele (GLS1 hets) are remarkably normal. Strikingly, functional imaging reveals that the mice have focal hypometabolism in the hippocampus, mainly involving the CA1 subregion and the subiculum that is the exact inverse of recent imaging findings in patients with schizophrenia. Moreover, when challenged with pro-psychotic drugs, GLS1 het mice manifest behavioral and neurochemical phenotypes consistent with schizophrenia resilience. Thus, reducing glutaminase activity appears to have therapeutic potential for schizophrenia. To translate this discovery to clinical application, we propose testing the hypothesis that GLS1 het mice are in fact resilient to a range of pro-schizophrenic insults. Using tissue-specific GLS1 deletions, we will ask whether the hippocampal hypometabolism arises from the reduction in GLS1 in the hippocampus, and whether this modulation is sufficient to produce the resilience phenotype. To begin to understand the implications of the resilience phenotype for the pathophysiology of schizophrenia, we will identify the synaptic alterations in the hippocampus that underlie the hypoactivity profile. To test the therapeutic potential of GLS1 inhibition directly, we will induce GLS1 haploinsufficiency in adult mice, doing what we term genetic-pharmacotherapy, to investigate the acute and chronic effects of the intervention. We will induce GLS1 haploinsufficiency earlier in development to explore potential benefits of early intervention and neurodevelopmental contributions. Finally, we will do high-throughput screening to identify small-molecule GLS1 inhibitors with nanomolar efficacy as drug candidates. GLS1 inhibition has therapeutic potential not only for schizophrenia, but also for stroke, and other neurodegenerative disorders involving excitotoxicity, so a CNS-active GLS1 inhibitor will likely have broad therapeutic promise. In summary, the planned preclinical studies together with identification of drug candidates should provide the basis for movement of GLS1 inhibition towards clinical trials as a novel pharmacotherapy for schizophrenia.

描述（由申请人提供）：谷氨酸能神经递质失调的非调节性与精神分裂症的心理病理学有关。最近的研究强调了谷氨酸传播突触前减少的治疗诺言。我们已经表明，来自谷氨酰胺酶（GLS1）基因敲除小鼠的神经元显示谷氨酸能突触传播的活性依赖性突触前还原。尽管GLS1敲除小鼠出生后不久死亡，但具有一个功能性GLS1等位基因（GLS1 HET）的GLS1单倍弹性小鼠非常正常。引人注目的是，功能成像表明，小鼠在海马中具有局灶性低代谢，主要涉及CA1次区域和皮下的下图，这是精神分裂症患者最近成像发现的确切反向。此外，当受到促性精神药物的挑战时，GLS1 HET小鼠表现出与精神分裂症韧性一致的行为和神经化学表型。因此，还原性谷氨酰胺酶活性似乎具有精神分裂症的治疗潜力。为了将这一发现转化为临床应用，我们提出了检验以下假设：GLS1 HET小鼠实际上对一系列促成schizizizophrenrencrenrenig侮辱性的弹性有弹性。使用组织特异性的GLS1缺失，我们将询问海马低代谢是否是由于海马中GLS1的减少产生的，以及该调节是否足以产生弹性表型。为了开始理解弹性表型对精神分裂症的病理生理学的影响，我们将确定海马中的突触改变，这是构成不连续性特征的基础的。为了直接测试GLS1抑制的治疗潜力，我们将在成年小鼠中诱导GLS1单倍症，从事我们称为遗传学疗法的事情，以研究干预的急性和慢性作用。我们将在开发过程中引起GLS1单倍症，以探索早期干预和神经发育贡献的潜在益处。最后，我们将进行高通量筛选，以鉴定具有纳摩尔功效为候选药物的小分子GLS1抑制剂。 GLS1抑制作用不仅具有精神分裂症的治疗潜力，而且对中风以及其他涉及兴奋性毒性的神经退行性疾病，因此CNS活性GLS1抑制剂可能会具有广泛的治疗前景。总之，计划的临床前研究以及鉴定候选药物的鉴定应为GLS1抑制向临床试验的运动提供基础，作为一种新型的精神分裂症药物治疗。