Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
基本信息
- 批准号:8599140
- 负责人:
- 金额:$ 180.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-18 至 2014-08-14
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgonistAnabolic steroidsAnimalsAntipsychotic AgentsAttentionBindingBiological AssayBiological MarkersBlood drug level resultBrainBrain imagingChemicalsChronicClinical ResearchClinical TrialsCognitiveCognitive deficitsCognitive remediationConsensusDataDoseDouble-Blind MethodEnvironmentEvent-Related PotentialsExerciseFunctional Magnetic Resonance ImagingGLYT1GlycineGoalsHumanImageImpaired cognitionInfusion proceduresInhibitory Concentration 50KetamineLifeLigandsLong-Term PotentiationMeasuresMemoryN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuronal PlasticityOutcome MeasurePatientsPharmaceutical PreparationsPhasePlacebo ControlPlacebosPlasmaPositron-Emission TomographyRandomizedRegulationRisperidoneSchizophreniaShort-Term MemorySiteSynapsesSynaptic plasticitySystemTestingTherapeuticTreatment EfficacyVisualaripiprazoleattenuationcognitive functiondisabilityeffective therapyefficacy testingfunctional disabilityglycine transporterin vivoindexinginhibitor/antagonistinnovationnovelnovel therapeuticspre-clinicalpreclinical studypublic health relevancereceptor functionresponsetranslational neurosciencetreatment response
项目摘要
DESCRIPTION (provided by applicant): Background: Cognitive impairments, for which there are no effective treatments, contribute significantly to functional disability in schizophrenia. Th goal of this application is to use a translational neuroscience approach to develop a treatment for the cognitive impairments associated with schizophrenia (CIAS). Deficits in NMDA receptor (NMDAR) function contribute to the CIAS and therefore, facilitation of NMDA-R function is one potential treatment approach for CIAS. Glycine transporter inhibitors (GlyT1Is) can enhance NMDAR related plasticity by raising synaptic glycine levels and stimulating the GlycineB co-agonist site of NMDARs. Preclinical data support the potential of GlyT1Is as treatments for the CIAS. PF-03463275 is a Glyt1I inhibitor that has not been tested for treatment of the CIAS. Higher doses of Glyt1Is including PF-03463275 may have a plateauing and/or worsening of effects suggestive of an inverted 'U' dose response. Therefore, it is critical for the optimal therapeutic dose range of GlyT1Is. UH2: The goal of the UH2 is to determine the best dose of PF-03463275. We will use positron emission tomography (PET) imaging to determine the dose-related occupancy of F-03463275 in order to determine whether it reaches its intended target and produces sufficient occupancy to be effective. In parallel, we will use fMRI as an assay of the dose-related GlyT1I facilitation of NMDAR function; we will determine whether PF-03463275 produces dose-related attenuation of the ketamine-induced disruption in prefrontal cortical BOLD activation related to working memory. UH2 Approach: 24 healthy subjects will receive placebo or two active doses of PF-03463275 BID for one week each during each of which, they will undergo a PET scan, long-term potentiation (LTP) session and a Ketamine-fMRI challenge study. UH3: In this phase (UH3), we will test the efficacy of PF-03463275 for CIAS in a novel proof of concept, double-blind, placebo-controlled, between-group study. Pharmacological enhancement of plasticity may not be sufficient to remediate long-standing cognitive dysfunction in the presence of the typical impoverished cognitive environment that patients live in. Therefore, just as physical exercise might optimize the effects of anabolic steroids, this trial wil combine cognitive remediation with PF-03463275 treatment. UH3 Approach: Schizophrenia subjects (n=76) taking risperidone or aripiprazole will be randomized to receive either placebo or active PF-03463275 BID in addition to cognitive remediation. Change in CAIS will be assessed using the Matrics Consensus Cognitive Battery composite score. We will also use visual Long Term Potentiation (LTP), an in vivo measure of NMDA-R-dependent synaptic plasticity, as a novel biomarker of the mechanism of action of PF-03463275. Using this approach, we propose to identify PF-03463275 effects on plasticity as indexed by LTP and to evaluate the capacity of PF- 03463275 to restore this form of neuroplasticity in schizophrenia patients, in whom it is deficient.
描述(由申请人提供):背景:没有有效治疗的认知障碍,对精神分裂症的功能障碍有显着贡献。该应用的目标是使用转化神经科学方法来开发与精神分裂症相关的认知障碍(CIAS)的治疗方法。 NMDA受体(NMDAR)功能的缺陷有助于CIAS,因此,NMDA-R功能的促进是CIAS的一种潜在治疗方法。甘氨酸转运蛋白抑制剂(GLYT1IS)可以通过提高突触甘氨酸水平并刺激NMDAR的甘氨酸共同激动剂来增强NMDAR相关的可塑性。临床前数据支持Glyt1is作为CIA的治疗的潜力。 PF-03463275是一种尚未测试用于治疗CIA的Glyt1i抑制剂。包括PF-03463275在内的较高剂量的Glyt1is可能具有平稳性和/或恶化的作用,提示倒置的“ U”剂量反应。因此,对于最佳治疗剂量范围至关重要。 UH2:UH2的目标是确定PF-03463275的最佳剂量。我们将使用正电子发射断层扫描(PET)成像来确定F-03463275与剂量相关的占用率,以确定其是否达到其预期目标并产生足够的占用率以有效。同时,我们将使用fMRI作为NMDAR功能的剂量相关Glyt1i促进的测定。我们将确定PF-03463275是否会导致氯胺酮诱导的与工作记忆相关的前额叶皮层大胆激活中剂量相关的衰减。 UH2方法:24名健康受试者将接受安慰剂或两种主动剂量的PF-03463275竞标,每周一周,他们将接受PET扫描,长期增强(LTP)会议和氯胺酮 - FMRI挑战赛研究。 UH3:在此阶段(UH3),我们将在新的概念证明中测试PF-03463275对CIA的功效,双盲,安慰剂控制,组间研究。在患者居住的典型贫困认知环境的存在下,可塑性的药理增强可能不足以补救长期的认知功能障碍。因此,正如体育锻炼可能优化了合成固醇类固醇的作用一样,该试验WIL将认知能力与PF-03463275治疗相结合。 UH3方法:服用利培酮或阿立哌唑的精神分裂症受试者(n = 76)将被随机分配,以接受安慰剂或主动PF-03463275竞标。 CAI的变化将使用Matrics共识认知电池综合评分进行评估。 我们还将使用视觉长期增强(LTP),这是NMDA-R依赖性突触可塑性的体内度量,作为PF-03463275作用机理的新生物标志物。使用这种方法,我们建议鉴定PF-03463275对可塑性的影响,如LTP所指数,并评估PF-03463275在精神分裂症患者中恢复这种形式的神经可塑性的能力,而精神分裂症患者的神经可塑性不足。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
John H. Krystal其他文献
617 - Dose-related ethanol effects in schizophrenic patients
- DOI:
10.1016/s0920-9964(97)82625-4 - 发表时间:
1997-01-01 - 期刊:
- 影响因子:
- 作者:
Edward Zuzarte;D. Cyril D’Souza;Roberto Gil;Alicia Genovese;Jonathan White;Dennis S. Charney;John H. Krystal - 通讯作者:
John H. Krystal
Effects of rapid tryptophan depletion in patients with seasonal affective disorder in remission after light therapy.
快速色氨酸消耗对光疗后缓解的季节性情感障碍患者的影响。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:0
- 作者:
Raymond W. Lam;A. Zis;A. Grewal;Pedro L. Delgado;Dennis S. Charney;John H. Krystal - 通讯作者:
John H. Krystal
507 - In vivo evaluation of dopamine synaptic funcflon in untreated schizophrenic patients
- DOI:
10.1016/s0920-9964(97)82515-7 - 发表时间:
1997-01-01 - 期刊:
- 影响因子:
- 作者:
Marc Laruelle;Anissa Abi-Dargham;John H. Krystal;Dennis S. Charney;Robert B. Innis - 通讯作者:
Robert B. Innis
T69. CPG AND NON-CPG EPIGENOMIC MAPPING IN HUMAN CORTICAL NEURONS REVEALS HYDROXYMETHYLATION AS AN IMPORTANT GENE REGULATORY MECHANISM IN PTSD
- DOI:
10.1016/j.euroneuro.2022.07.369 - 发表时间:
2022-10-01 - 期刊:
- 影响因子:
- 作者:
Diana Nunez;Gregory Rompala;Yasmin Hurd;Sheila T. Nagamatsu;Jose Jaime Martínez-Magaña;John H. Krystal;Joel Gelernter;Janitza L. Traumatic Stress Brain Research Group; Montalvo-Ortiz - 通讯作者:
Montalvo-Ortiz
618 - Evaluation of lorazepam blockade of M-chlorophenylpiperazine (MCPP) effects in schizophrenia
- DOI:
10.1016/s0920-9964(97)82626-6 - 发表时间:
1997-01-01 - 期刊:
- 影响因子:
- 作者:
Edward Zuzarte;D. Cyril D’Souza;Roberto Gil;Jonathan White;Danielle AbiSaab;Dennis S. Charney;John H. Krystal - 通讯作者:
John H. Krystal
John H. Krystal的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('John H. Krystal', 18)}}的其他基金
The 4th International Conference on Applications of Neuroimaging to Alcoholism (ICANA-4)
第四届酒精中毒神经影像学应用国际会议 (ICANA-4)
- 批准号:
9761789 - 财政年份:2019
- 资助金额:
$ 180.8万 - 项目类别:
Yale Clinical and Translational Science Award: Nwanaji-Enwerem Diversity in Health Related Research
耶鲁大学临床和转化科学奖:健康相关研究的 Nwanaji-Enwerem 多样性
- 批准号:
10733278 - 财政年份:2016
- 资助金额:
$ 180.8万 - 项目类别:
Yale Clinical and Translational Science Award: Calhoun Diversity in Health Related Research
耶鲁临床和转化科学奖:卡尔霍恩健康相关研究多样性
- 批准号:
10518169 - 财政年份:2016
- 资助金额:
$ 180.8万 - 项目类别:
Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
- 批准号:
8913287 - 财政年份:2013
- 资助金额:
$ 180.8万 - 项目类别:
Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
- 批准号:
8823969 - 财政年份:2013
- 资助金额:
$ 180.8万 - 项目类别:
相似国自然基金
内源激动剂ArA靶向TMEM175蛋白缓解帕金森病症的分子机制研究
- 批准号:32300565
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
Adrb2激动剂在改善呼吸机相关性膈肌功能障碍中的作用与机制研究
- 批准号:82372196
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
新型IL2Rβγ激动剂逐级控释联合放疗对抗三阴性乳腺癌的作用及机制研究
- 批准号:82303819
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于OSMAC-GNPS分析策略的蚂蚱内生真菌Aspergillus sp.中新颖泛PPAR激动剂的发现及治疗NASH研究
- 批准号:82304340
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
探究FSP1激动剂在治疗肾缺血再灌注损伤中的分子机理与应用
- 批准号:82304600
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
- 批准号:
8913287 - 财政年份:2013
- 资助金额:
$ 180.8万 - 项目类别:
Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
- 批准号:
8823969 - 财政年份:2013
- 资助金额:
$ 180.8万 - 项目类别:
Translational Neuroscience Optimization of GlyT1 Inhibitor
GlyT1 抑制剂的转化神经科学优化
- 批准号:
8768830 - 财政年份:2013
- 资助金额:
$ 180.8万 - 项目类别:
EFFECT OF ANDROGENS ON BEHAVIOR THROUGH NPY MODULATION
雄激素通过 NPY 调节对行为的影响
- 批准号:
8360152 - 财政年份:2011
- 资助金额:
$ 180.8万 - 项目类别:
Anabolic-androgenic steroids promote risky decision making
合成代谢雄激素类固醇促进危险决策
- 批准号:
9026543 - 财政年份:2011
- 资助金额:
$ 180.8万 - 项目类别: