Potentiate Cav3.3 To Treat Cognitive Deficits Associated with Impaired Sleep Spindle

增强 Cav3.3 治疗与睡眠纺锤体受损相关的认知缺陷

• 批准号: 10793677
• 负责人: Jen Qian Pan
• 金额: $ 39万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10793677
• 关键词: ATP2A2; Address; Affect; Alzheimer' s disease patient; Attention; Behavioral; Behavioral Assay; Biological; Biological Assay; Biological Markers; Biology; Brain; Calcium Channel; Cell Nucleus; Central Nervous System Diseases; Chemicals; Cognition; Cognitive; Cognitive deficits; Critical Pathways; Cryoelectron Microscopy; Data; Drug Kinetics; Etiology; Evaluation; Exhibits; Fluorescence; Frequencies; Functional disorder; Future; Gene Expression Profile; Generations; Genetic; Hallucinations; Human Genetics; Impaired cognition; Impairment; Individual; Investigational Drugs; Ion Channel; Lead; Ligand Binding; Maps; Measures; Memory; Mental disorders; Mentally Disabled Persons; Metabolic; Mission; Molecular; Mus; Mutation; Neurons; Parvalbumins; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Play; Population; Property; Reagent; Reproducibility; Resolution; Risk; Role; Schizophrenia; Series; Short-Term Memory; Sleep; Sleep disturbances; Slice; Solubility; Structure; Symptoms; Thalamic Nuclei; Thalamic structure; Therapeutic; Translating; Validation; Waxes; clinical development; cognitive function; cognitive performance; de novo mutation; density; design; drug candidate; flexibility; high throughput screening; human disease; improved; improvement on sleep; in vivo; lead optimization; memory consolidation; mouse model; multidisciplinary; nervous system disorder; neuronal excitability; neurophysiology; non rapid eye movement; novel; novel drug class; novel therapeutics; patient population; pharmacodynamic biomarker; pharmacologic; pre-clinical; preclinical development; rational design; risk variant; scaffold; schizophrenia risk; severe psychiatric disorder; side effect; sleep spindle; small molecule; success; voltage

Project Summary/Abstract Sleep spindle is a hallmark brain oscillation occurring in NREM (non-rapid eye movement) sleep that reflect intrinsic thalamocortical offline processing. Spindles are waxing and waning bursts of 12-15 Hz oscillations that originate in Thalamic Reticular Nucleus (TRN) when its neurons undergo bursting firing, and TRN- Thalamic Relay network oscillates at spindle frequency through the reciprocal connection. Sleep spindles are markedly reduced in schizophrenia patients as well as in Alzheimer patients, two very different CNS disorders yet both demonstrated significant altered sleep spindle properties associated with cognitive impairment. We hypothesize that hypofunctional TRN may underlie the risk/symptoms of these two devasting illnesses. CACNA1I is encode the α1 functional core of the CaV3.3 voltage-ˇgated calcium channels, and its expression is enriched in TRN. We have discovered two novel chemical scaffolds that potentiate CaV3.3 function, and this proposal aims to deliver in vivo ready Cav3.3 positive modulators. This multidisciplinary effort is expected to yield a panel of incisive pharmacological reagents to enhance CaV3.3 function in the brain and nominate candidates for preclinical development for treating cognitive impairments in schizophrenia patients.

项目摘要/摘要 睡眠纺锤体是NREM(非快速眼动)睡眠中出现的一种标志性大脑振荡，它反映了 固有的丘脑皮质脱机处理。纺锤体是12-15赫兹振荡的增减脉冲 起源于丘脑网状核(TRN)，当其神经元经历爆发式放电时，TRN- 丘脑中继网络通过相互连接以纺锤频率振荡。睡眠纺锤体是 精神分裂症患者和阿尔茨海默病患者的显著减少，这两种截然不同的中枢神经系统疾病 然而，两者都显示出与认知障碍相关的睡眠纺锤特性的显著改变。我们 假设TRN功能低下可能是这两种致命疾病的风险/症状的基础。 CACNA1I编码α1功能核心的CaV3.3电压-ˇ门控钙通道，并表达 富含TRN。我们发现了两种新型的化学支架，它们可以增强CaV3.3的功能，而这 该提案旨在提供体内准备好的CaV3.3正向调节器。这一多学科的努力预计将 产生一组尖锐的药理试剂以增强大脑中CaV3.3的功能并提名 治疗精神分裂症患者认知障碍的临床前开发的候选者。