Circadian Regulation of Cellular Homeostasis

细胞稳态的昼夜节律调节

• 批准号: 10592417
• 负责人: Weston W Porter
• 金额: $ 50.38万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-18 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592417
• 关键词: Address; Adult; Affect; Basal Cell; Behavior; Biological Clocks; Biological Models; Breast Epithelial Cells; Cell Differentiation process; Cell Lineage; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Data; Development; Disease; Down-Regulation; Duct (organ) structure; Embryonic Development; Environment; Etiology; Eye; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Health; Heterogeneity; Homeostasis; Hormones; Intervention; Jet Lag Syndrome; Lactation; Light; MCF10A cells; Malignant Neoplasms; Mammary gland; Metabolic Diseases; Metabolism; Modeling; Molecular; Morphogenesis; Mus; Organism; Periodicity; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Play; Population; Pregnancy; Process; Proliferating; Puberty; Regulation; Reporter; Risk; Role; Sensory; Signal Transduction; Sleep; Sleep Disorders; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Differentiation; Transforming Growth Factor beta; Vulnerable Populations; WNT Signaling Pathway; Working Women; beta catenin; cancer stem cell; cell behavior; cell growth regulation; cell type; circadian; circadian pacemaker; circadian regulation; differential expression; malignant breast neoplasm; mammary; mammary epithelium; mammary gland development; neurotransmitter release; novel; self-renewal; shift work; single-cell RNA sequencing; social; stem; stem cell biology; stem cell fate; stem cell homeostasis; stem cells; stroke risk; transcription factor; Address; Adult; Affect; Basal Cell; Behavior; Biological Clocks; Biological Models; Breast Epithelial Cells; Cell Differentiation process; Cell Lineage; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Data; Development; Disease; Down-Regulation; Duct (organ) structure; Embryonic Development; Environment; Etiology; Eye; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Health; Heterogeneity; Homeostasis; Hormones; Intervention; Jet Lag Syndrome; Lactation; Light; MCF10A cells; Malignant Neoplasms; Mammary gland; Metabolic Diseases; Metabolism; Modeling; Molecular; Morphogenesis; Mus; Organism; Periodicity; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Play; Population; Pregnancy; Process; Proliferating; Puberty; Regulation; Reporter; Risk; Role; Sensory; Signal Transduction; Sleep; Sleep Disorders; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Differentiation; Transforming Growth Factor beta; Vulnerable Populations; WNT Signaling Pathway; Working Women; beta catenin; cancer stem cell; cell behavior; cell growth regulation; cell type; circadian; circadian pacemaker; circadian regulation; differential expression; malignant breast neoplasm; mammary; mammary epithelium; mammary gland development; neurotransmitter release; novel; self-renewal; shift work; single-cell RNA sequencing; social; stem; stem cell biology; stem cell fate; stem cell homeostasis; stem cells; stroke risk; transcription factor

Biological clocks play a key role in how organisms adapt to daily (circadian), monthly (circalunar), and annual (circannual) changes in the environment by regulating rhythmic fluctuations in metabolism, hormone and neurotransmitter release, sensory capabilities and behaviors, including sleep. Disruption of circadian rhythms (e.g. shift work, time zone changes (“jet lag”), or social jet lag), can result in significant physiological consequences including sleep and metabolic disorders, as well as increased risk of stroke and cancer. Recent data indicate that the circadian clock is developmentally regulated and that its time-keeping activity is suspended in differentiating tissues to allow clock components to function in a “developmental clock”, that regulates stem/progenitor cell biology and differentiation, among other processes. However, it is not known how this functional shift from circadian to developmental activities is achieved, nor is it known how clock components control normal or malignant stem/progenitor cell behaviors. The mouse mammary gland is a powerful models system for the study of circadian rhythms, development, and stem/progenitor cell biology. Lineage tracing studies have demonstrated that the mammary gland harbors dynamic cell populations in which self-renewing unipotent basal and luminal stem cell lineages give rise to their respective lineages during ductal elongation, and are responsible for breast cancer cellular heterogeneity. We have shown that PER2, a transcription factor in the circadian clock, is differentially expressed during mammary gland development, and is required for branching morphogenesis, suggesting a circadian clock-independent developmental role. Our recent data using Per2-/- mouse mammary glands suggest that PER2 may play a critical role in mammary epithelial cell lineage commitment and homeostasis, and may do so by regulating the expression of EYA2 as well as influencing Wnt/b-catenin and TGF-b signaling. Moreover, we have found that circadian disruption in mice results in down regulation of Per2 expression in mammary epithelial cells and increased EYA2 expression and activation of Wnt/b-catenin. Based on these new results, we hypothesize that PER2 functions to integrate the circadian clock with the developmental clock to control homeostasis of mammary epithelial cell types during ductal elongation and branching morphogenesis. To address this hypothesis three Specific Aims are proposed. Aim 1 will test circadian and circadian disruption dependent changes in stem and progenitor cells in the developing mammary gland. Aim 2 will focus on the role of PER2 in lineage commitment using genetic reporters to trace mammary cell differentiation and examine the effect of PER2 on stem cell homeostasis. Studies in Aim 3 will determine PER2-dependent regulation of EYA2 gene expression and regulation of b-catenin in mammary gland morphogenesis. Upon successful completion of this aim we will have a better understanding of the molecular mechanisms that govern the interaction of PER2 and EYA2 as well as the effect on WNT/ TGFb signaling in branching morphogenesis.

生物钟在生物体适应日常（昼夜节律），每月（圆形）和年度的生物时钟起着关键作用 （大通）通过规范代谢，骑马和 神经递质释放，感觉能力和行为，包括睡眠。昼夜节律的破坏 （例如，轮班工作，时区变化（“喷气滞后”）或社交喷气滞后）可能会导致重要的生理 后果包括睡眠和代谢疾病，以及中风和癌症的风险增加。最近的 数据表明昼夜节律受到了调节，其时间保持活动是 暂停以区分时间安排，以允许时钟组件在“发育时钟”中起作用， 调节茎/祖细胞生物学和分化等其他过程。但是，这是不知道的 如何实现从昼夜节律到发展活动的功能转变，也不知道如何时钟 组件控制正常或恶性茎/祖细胞行为。小鼠乳腺是 强大的模型系统，用于研究昼夜节律，发育和茎/祖细胞生物学。 谱系追踪研究表明，乳腺具有动态细胞种群，其中 自我更新一能碱性和管腔干细胞谱系在导管期间产生各自的谱系 伸长，并负责乳腺癌细胞异质性。我们已经证明了Per2，一个 昼夜节律中的转录因子在乳腺发育过程中差异表达，并且 分支形态发生需要，表明昼夜节律与时钟无关的发育作用。我们的 使用PER2 - / - 小鼠乳腺的最新数据表明，PER2可能在乳腺中起关键作用 上皮细胞谱系承诺和稳态，并且可以通过调节Eya2的表达来做到这一点 以及影响Wnt/B-catenin和TGF-B信号传导。此外，我们发现昼夜节律中断 小鼠导致乳腺上皮细胞中PER2表达的调节，并增加EYA2表达 Wnt/B-catenin的激活。基于这些新结果，我们假设PER2功能可以集成 带有发育时钟的昼夜节律，以控制乳腺上皮细胞类型的体内 导管伸长和分支形态发生。为了解决这一假设，提出了三个具体目标。 AIM 1将测试昼夜节律和昼夜节律依赖于茎和祖细胞的变化 发展乳腺。 AIM 2将专注于PER2在使用遗传记者的谱系承诺中的作用 追踪乳腺细胞分化并检查PER2对干细胞稳态的影响。研究 AIM 3将确定eya2基因表达的PER2依赖性调节和B-catenin中的调节 乳腺形态发生。成功完成此目标后，我们将有更好的理解 控制PER2和EYA2相互作用的分子机制以及对Wnt/的影响 分支形态发生中的TGFB信号传导。