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

基本信息

批准号：
10566385
负责人：
Jen Qian Pan
金额：
$ 71.7万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566385
关键词：
ATP2A2 Address Affect Alzheimer&apos s disease patient Attention Back 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 Ligands Maps Measures Memory Mental disorders Metabolic Mission Molecular Mus Mutation Neurons Parvalbumins Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology 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 base clinical development cognitive function cognitive performance de novo mutation density design drug candidate flexibility high throughput screening human disease improved 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 pre-clinical preclinical development rational design risk variant scaffold schizophrenia risk severe psychiatric disorder side effect sleep spindle small molecule success voltage

ATP2A2 Address Affect Alzheimer&apos s disease patient Attention Back 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 Ligands Maps Measures Memory Mental disorders Metabolic Mission Molecular Mus Mutation Neurons Parvalbumins Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology 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 base clinical development cognitive function cognitive performance de novo mutation density design drug candidate flexibility high throughput screening human disease improved 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 pre-clinical preclinical development rational design risk variant scaffold schizophrenia risk severe psychiatric disorder side effect sleep spindle small molecule success voltage

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项目摘要

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/摘要睡眠主轴是在NREM（非拉皮眼运动）睡眠中发生的标志性脑振荡固有的丘脑皮层离线处理。纺锤的上蜡和减弱的爆发12-15 Hz振荡当它的神经元发生爆发时，该核核（TRN）起源于丘脑的网状核（TRN）丘脑继电器网络通过相互连接在主轴频率下振荡。睡眠主轴是精神分裂症患者以及阿尔茨海默氏症患者中有明显降低，两种非常不同的中枢神经系统疾病然而，两者都表现出与认知障碍相关的睡眠纺锤体特性的显着改变。我们假设功能性TRN可能是这两种破坏性疾病的风险/症状的基础。 cacna1i被编码Cav3.3电压钙通道的α1功能核心及其表达在TRN中富含。我们发现了两个潜在Cav3.3功能的新型化学支架，这提案旨在提供体内现成的CAV3.3阳性调节剂。这项多学科的工作有望产生一系列尖锐的药物试剂，以增强CAV3.3大脑的功能并提名用于治疗精神分裂症患者认知障碍的临床前发展的候选者。