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：
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
项目类别：
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&apos 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

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.

项目概要/摘要睡眠纺锤波是 NREM（非快速眼动）睡眠中发生的标志性脑振荡，反映了丘脑皮质的内在离线处理纺锤体呈 12-15 Hz 振荡的增减爆发。起源于丘脑网状核 (TRN)，当其神经元经历爆发性放电时，TRN- 丘脑中继网络通过睡眠主轴的相互连接以主轴频率振荡。在精神分裂症患者和阿尔茨海默病患者中显着减少，这是两种截然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显着睡眠纺锤体特性。 TRN 功能低下可能是这两种毁灭性疾病的风险/症状的根源。 CACNA1I编码CaV3.3电压门控钙通道的α1功能核心，其表达我们发现了两种增强 CaV3.3 功能的新型化学支架。该提案旨在提供体内就绪的 Cav3.3 正调节剂。这项多学科努力预计将实现这一目标。产生一组敏锐的药理学试剂来增强大脑中的 CaV3.3 功能并提名用于治疗精神分裂症患者认知障碍的临床前开发候选药物。