Role of Clock-Modulating Small Molecules Against Aging

时钟调节小分子抗衰老的作用

基本信息

批准号：
8580451
负责人：
Zheng Chen
金额：
$ 24.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580451
关键词：
Acute Address Adipose tissue Adopted Affinity Aging Aging-Related Process Attenuated Behavioral Biological Bioluminescence Body Temperature Cells Chronic Chronic Disease Circadian Rhythms Data Devices Diet Elderly Energy Metabolism Exhibits Fatty acid glycerol esters Functional disorder Gene Expression Profile Genetic Genome Health Homeostasis Hormones In Vitro Insulin Knowledge Life Expectancy Liver Measures Mediating Metabolic Metabolic syndrome Modeling Molecular Molecular Probes Mus Obesity Output Pathway interactions Personal Satisfaction Pharmaceutical Preparations Physiological Population Positioning Attribute Process Proteins Regulation Reporter Resistance Role Sampling Sleep Fragmentations Tissues age related aged anti aging arm attenuation circadian pacemaker environmental change functional decline healthy aging high throughput screening improved in vivo insight mutant public health relevance response small molecule social tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): With the rising life expectancy and elderly population in the US, how to achieve healthy aging and extend health span is a pressing biomedical question with profound social ramifications. A pivotal biological mechanism governing our well-being is the circadian clock, the intrinsic timekeeping device that responds to environmental changes and coordinates bodily functions throughout the 24-h cycles. Accumulating evidence has demonstrated a strong correlation between aging and circadian dysfunctions, particularly attenuation of circadian rhythms such as sleep fragmentation and reduced amplitude of body temperature and circulating hormone cycles. We recently identified a unique group of Clock-Enhancing small Molecules, now dubbed as CEMs, via high-throughput screening. To investigate the potential causal role of clock attenuation in aging, we will address the hypothesis that CEMs can improve aged clocks and age-related metabolic decline. We focus on energy metabolism because it is closely regulated by the clock and aging is associated with significant decline in energy utilization. Three Specific Aims are proposed. Specific Aim 1: Determine the clock mechanism of CEMs in aged mice. Using aged PER2::luc reporter mice, we will determine whether CEMs can enhance the bioluminescence rhythm at tissue and single-cell levels. To understand the molecular mechanism, we will systematically characterize the core clock loops in aged tissues, and dissect transcriptional and posttranscriptional mechanisms underlying CEM-mediated enhancement of aged clocks. Specific Aim 2: Delineate the role of CEMs in age-related metabolic decline. We will determine whether CEMs can enhance energy metabolism in naturally aged mice by molecular and physiological approaches. To define the molecular mechanism of CEMs in energy homeostasis of aged mice, we will screen candidate metabolic regulators for altered expression or activity in response to CEM treatment, and investigate the metabolic regulatory mechanisms by CEMs in aged mice. Specific Aim 3: Identify the cellular networks and direct targets of CEMs. To identify both chronic and acute cellular responses to CEMs in aged mice, we will conduct RNA-seq transcriptome profiling using samples from aged mice treated with CEMs for varying periods. To identify direct targets, we will carry out chemoproteomic studies involving affinity pull-down with biotinylated CEM derivatives. Anti-aging roles of specific cellular pathways and proteins from these studies will be further investigated by pharmacological and genetic approaches. Successful completion of these Aims will address the critical question regarding a causal role of clock attenuation during aging and reveal an exciting efficacy of CEMs in prolonging health span.

描述（申请人提供）：随着美国预期寿命和老年人口的不断增加，如何实现健康老龄化和延长健康寿命是一个紧迫的生物医学问题，具有深远的社会影响。控制我们健康的一个关键生物机制是生物钟，它是一种内在的计时装置，可以在 24 小时周期内响应环境变化并协调身体功能。越来越多的证据表明，衰老与昼夜节律功能障碍之间存在很强的相关性，特别是昼夜节律的减弱，例如睡眠碎片化以及体温和循环激素周期幅度降低。我们最近通过高通量筛选鉴定了一组独特的时钟增强小分子，现在称为 CEM。为了研究时钟衰减在衰老中的潜在因果作用，我们将提出以下假设 CEM 可以改善衰老的生物钟和与年龄相关的代谢下降。我们关注能量代谢，因为它受到生物钟的密切调节，而衰老与能量利用率的显着下降有关。提出了三个具体目标。具体目标 1：确定老年小鼠 CEM 的时钟机制。使用老年 PER2::luc 报告小鼠，我们将确定 CEM 是否可以增强组织和单细胞水平的生物发光节律。为了理解分子机制，我们将系统地表征衰老组织中的核心时钟环路，并剖析 CEM 介导的衰老时钟增强的转录和转录后机制。具体目标 2：描述 CEM 在与年龄相关的代谢下降中的作用。我们将通过分子和生理学方法确定 CEM 是否可以增强自然衰老小鼠的能量代谢。为了明确 CEM 在老年小鼠能量稳态中的分子机制，我们将筛选候选代谢调节因子，以响应 CEM 治疗而改变表达或活性，并研究 CEM 在老年小鼠中的代谢调节机制。具体目标 3：确定 CEM 的蜂窝网络和直接目标。为了确定老年小鼠对 CEM 的慢性和急性细胞反应，我们将使用接受不同时期 CEM 治疗的老年小鼠的样本进行 RNA-seq 转录组分析。为了确定直接靶标，我们将进行化学蛋白质组学研究，涉及生物素化 CEM 衍生物的亲和力下拉。这些研究中特定细胞途径和蛋白质的抗衰老作用将是通过药理学和遗传学方法进一步研究。成功完成这些目标将解决有关衰老过程中时钟衰减因果作用的关键问题，并揭示 CEM 在延长健康寿命方面令人兴奋的功效。