Role of Clock-Modulating Small Molecules Against Aging

时钟调节小分子抗衰老的作用

• 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
• 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

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（由申请人提供）：随着美国的预期寿命和老年人口的不断增长，如何实现健康的衰老和延长健康跨度是一个紧迫的生物医学问题，具有深刻的社会影响。管理我们福祉的关键生物学机制是昼夜节律时钟，这是一种内在的计时装置，响应环境变化，并在整个24小时循环中辅助身体功能。积累的证据表明，衰老和昼夜节律功能障碍之间存在很强的相关性，尤其是昼夜节律的衰减，例如睡眠碎片，体温和循环激素循环的幅度降低。我们最近通过高通量筛选确定了一组独特的时钟增强小分子，现在称为CEMS。为了调查时钟衰减在衰老中的潜在因果作用，我们将解决该假设 CEM可以改善老化时钟和与年龄有关的代谢下降。我们专注于能源代谢，因为它受时钟的密切调节，并且衰老与能量利用率的显着下降有关。提出了三个具体目标。 特定目标1：确定老年小鼠CEM的时钟机制。使用老化的PER2 :: Luc Reporter小鼠，我们将确定CEM是否可以增强组织和单细胞水平下的生物发光节奏。为了理解分子机制，我们将系统地表征老化组织中的核心时钟环，并剖析CEM介导的增强型时钟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方法来确定CEM是否可以增强自然老化小鼠的能量代谢。为了定义老年小鼠能量稳态中CEMS的分子机制，我们将筛选候选代谢代谢调节剂，以改变对CEM治疗的表达或活性，并研究老年小鼠中CEM的代谢调节机制。 特定目标3：确定CEMS的细胞网络和直接目标。为了确定老年小鼠中对CEM的慢性和急性细胞反应，我们将使用来自CEMS处理的老年小鼠的样品进行RNA-Seq转录组分析。为了确定直接靶标，我们将进行涉及与生物素化CEM衍生物亲和力下拉的化学蛋白质组学研究。这些研究的特定细胞途径和蛋白质的抗衰老作用将是 通过药理和遗传方法进一步研究。 这些目标的成功完成将解决有关衰老过程中时钟衰减的因果作用的关键问题，并揭示了CEM在延长健康范围内的令人兴奋的功效。