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

• 批准号: 8210963
• 负责人: STEPHEN RAYPORT
• 金额: $ 35.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8210963
• 关键词: Acute; Address; Adult; Affect; Agonist; Alleles; Attenuated; Behavioral; Birth; Chronic; Clinical; Clinical Drug Development; Clinical Trials; Development; Development Plans; Early treatment; 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

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. PUBLIC HEALTH RELEVANCE: We have recently generated a coherent set of clinical and basic findings raising the hypothesis that pharmacological inhibition of phosphate-activated glutaminase, the product of gene GLS1, should prove therapeutic in schizophrenia. We propose to test this hypothesis using GLS1-deficient mice as a proof of concept. The aims are to gain insight into the therapeutic basis for GLS1 inhibition, to elucidate the circuitry involved, and to gain the necessary knowledge for moving toward clinical drug development.

描述（由申请人提供）：谷氨酸能神经传递失调与精神分裂症的精神病理学密切相关。最近的研究强调了突触前谷氨酸传输减少的治疗前景。我们已经证明，谷氨酰胺酶（GLS1）敲除小鼠的神经元表现出谷氨酸能突触传递的活动依赖性突触前减少。虽然 GLS1 敲除小鼠在出生后不久就会死亡，但具有一个功能性 GLS1 等位基因 (GLS1 hets) 的 GLS1 单倍体不足的小鼠却非常正常。引人注目的是，功能成像显示小鼠的海马体存在局灶性代谢低下，主要涉及 CA1 亚区和下托，这与精神分裂症患者最近的成像结果正好相反。此外，当受到促精神病药物的挑战时，GLS1 het 小鼠表现出与精神分裂症恢复力一致的行为和神经化学表型。因此，降低谷氨酰胺酶活性似乎具有治疗精神分裂症的潜力。为了将这一发现转化为临床应用，我们建议测试以下假设：GLS1 het 小鼠实际上对一系列促精神分裂症损伤具有弹性。使用组织特异性 GLS1 缺失，我们将询问海马代谢低下是否是由海马 GLS1 减少引起的，以及这种调节是否足以产生弹性表型。为了开始了解弹性表型对精神分裂症病理生理学的影响，我们将确定海马体中活动减退背后的突触改变。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 单倍体不足，进行我们所说的基因药物治疗，以研究干预措施的急性和慢性影响。我们将在发育早期诱导 GLS1 单倍体不足，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，以确定具有纳摩尔级功效的小分子 GLS1 抑制剂作为候选药物。 GLS1 抑制不仅对精神分裂症具有治疗潜力，而且对中风和其他涉及兴奋性毒性的神经退行性疾病也具有治疗潜力，因此 CNS 活性 GLS1 抑制剂可能具有广泛的治疗前景。总之，计划中的临床前研究以及候选药物的鉴定应该为 GLS1 抑制作为精神分裂症的新型药物疗法走向临床试验提供基础。 公共健康相关性：我们最近得出了一系列连贯的临床和基本发现，提出了这样的假设：磷酸激活谷氨酰胺酶（GLS1 基因的产物）的药理抑制应该可以治疗精神分裂症。我们建议使用 GLS1 缺陷小鼠作为概念证明来测试这一假设。目的是深入了解 GLS1 抑制的治疗基础，阐明所涉及的电路，并获得进行临床药物开发所需的知识。