Circadian dysfunction and GSK3 in neurodegenerative disease

神经退行性疾病中的昼夜节律功能障碍和 GSK3

基本信息

批准号：
9225246
负责人：
Karen L Gamble
金额：
$ 28.45万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2013-03-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9225246
关键词：
Aggressive behavior Agitation Alpha Rhythm Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Behavior Behavioral Body Temperature Brain region Caregiver Burden Circadian Dysregulation Circadian Rhythms Cognition Cognitive Cognitive deficits Comorbidity Confusion Darkness Data Delirium Dementia Development Enzymes Equilibrium Event Exhibits Foundations Functional disorder Future Gene Expression Glycogen Synthase Kinase 3 Hippocampus (Brain)Hyperactive behavior Impaired cognition Impairment Institutionalization Learning Link Lithium Mediating Mediator of activation protein Membrane Memory Mental disorders Molecular Molecular Abnormality Motor Activity Mus Nervous System Physiology Neurodegenerative Disorders Neurons Pathologic Patients Pattern Periodicity Phosphorylation Phosphotransferases Physiological Physiology Preparation Property Regulation Research Research Design Rest Series Symptoms Synapses Synaptic plasticity Syndrome Testing Therapeutic Time Variant circadian pacemaker cognitive function design experimental study inhibitor/antagonist innovation insight mouse model nervous system disorder public health relevance relating to nervous system suprachiasmatic nucleus synaptic function translational study

项目摘要

DESCRIPTION (provided by applicant): Behavioral disturbance and day-night rhythm disruption of dementia patients are top reasons for institutionalization and cause of caregiver burden. Patients with dementia or Alzheimer's disease often exhibit "sundowning syndrome," a constellation of symptoms including late afternoon/evening hyperactivity, restlessness, confusion, and aggression, along with misaligned core body temperature and activity rhythms. These symptoms suggest a dysregulated circadian network, which normally allows anticipation of and preparation for daily recurring environmental events, including time-of-day-specific variability in cognitive function. Identification of the molecular abnormalities underlying circadin dysregulation would allow for the development of targeted strategies for reinstating rhythmicity and associated behaviors. This project will test the hypothesis that glycogen synthase kinase 3 provides a time-of-day-specific gating mechanism for intrinsic excitability, and that disruptions i daily changes in the phosphorylation state balance of this enzyme within specific brain regions contribute to circadian and cognitive abnormalities of neurodegenerative disease. Specifically, this project will determine whether day-night changes in phosphorylation of glycogen synthase kinase 3 regulate oscillations of clock gene expression and physiology and that cognition and circadian behavioral abnormalities in neurodegenerative disease are mediated by loss of daily glycogen synthase kinase 3 phosphorylation cycles and dysregulated neural activity rhythms. Proposed studies will examine this hypothesis in the suprachiasmatic nucleus and hippocampus under normal physiologic conditions (Aim 1) as well as under pathological conditions (Aim 2) utilizing animal models of neurodegenerative disease. Successful completion of these experiments will establish glycogen synthase kinase 3 as a key player in day-night variation of membrane properties and synaptic physiology, which are critical for appropriately timed cognitive function and rest/activity patterns. They will also lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing in dementia and neurological disease.

描述（由申请人提供）：痴呆症患者的行为障碍和昼夜节律紊乱是入院的首要原因和护理人员负担的原因。痴呆症或阿尔茨海默病患者经常表现出“日落综合症”，这是一系列症状，包括下午晚些时候/晚上过度活跃、烦躁、混乱和攻击性，以及核心体温和活动节律失调。这些症状表明昼夜节律网络失调，该网络通常允许对每天重复发生的环境事件进行预期和准备，包括认知功能的特定时间变化。识别昼夜节律失调背后的分子异常将有助于制定恢复节律和相关行为的有针对性的策略。该项目将测试以下假设：糖原合酶激酶 3 为内在兴奋性提供了一天中特定时间的门控机制，并且特定大脑区域内该酶磷酸化状态平衡的日常变化的破坏会导致昼夜节律和认知异常神经退行性疾病。具体来说，该项目将确定糖原合酶激酶 3 磷酸化的昼夜变化是否调节时钟基因表达和生理学的振荡，以及神经退行性疾病中的认知和昼夜行为异常是由日常糖原合酶激酶 3 磷酸化周期的丧失和失调介导的神经活动节律。拟议的研究将利用神经退行性疾病的动物模型在正常生理条件下（目标 1）以及病理条件下（目标 2）检验视交叉上核和海马的这一假设。这些实验的成功完成将确立糖原合酶激酶 3 作为膜特性和突触生理学昼夜变化的关键参与者，这对于适当定时的认知功能和休息/活动模式至关重要。他们还将为旨在针对这一机制的转化研究奠定基础，以便在痴呆和神经系统疾病中找到适当的治疗时机。