Role of TGF-β signaling for coupling of circadian oscillators in peripheral tissues

TGF-β 信号传导在外周组织中昼夜节律振荡器耦合中的作用

• 批准号: 430682294
• 负责人: Professor Dr. Achim Kramer
• 金额: --
• 依托单位: Fachbereich Chronobiologie (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/430682294?language=en
• 关键词: Role; TGF; signaling; coupling; circadian

It has long been known that coupling among circadian oscillator cells in the suprachiasmatic nucleus is required for cohesive, robust and high amplitude rhythms. However, whether coupling also exists between cellular clocks in the periphery was controversial, and a possible mechanism was unknown. Recently, the Schibler laboratory was able to show unequivocally that peripheral oscillator cells (hepatocytes) are also coupled in living mice. At the same time, we have identified canonical TGF-β signaling as a pathway required for normal coupling of cellular circadian clocks in peripheral cells. Here, we hypothesize that canonical TGF-β signaling contributes to intercellular coupling of hepatocytes in vivo thereby playing an important role for circadian physiology. To test this hypothesis, we propose to study the following two objectives: Objective 1: Characterize the role of canonical TGF-β signaling for coupling of hepatocytes in vivo Impairment of coupling within peripheral tissues is predicted to affect cohesiveness, amplitudes, phases as well as responses to zeitgebers. We will create tissue-specific genetic loss-of-function mouse models of canonical TGF-β signaling and test (i) whether circadian amplitudes and phases of clock genes and clock-controlled genes are affected; (ii) whether the kinetics of phase shifting upon feeding reversal is altered. Objective 2: Study the role of canonical TGF-β signaling for liver transcriptome rhythms As gene expression rhythms in peripheral tissues depend on both the local circadian oscillator and rhythmic systemic zeitgebers, a perturbation of coupling likely affects circadian dynamics of gene expression due to a potentially altered response to systemic inputs. We will analyze circadian gene expression rhythms in murine liver with perturbed canonical TGF-β signalling in hepatocytes and identify potentially affected physiological pathways.

人们早就知道视交叉上核中的昼夜节律振荡细胞之间的耦合是内聚、稳健和高振幅节律所必需的，但是，外周细胞时钟之间是否也存在耦合存在争议，并且最近尚不清楚其可能的机制。 Schibler 实验室能够明确地表明，外周振荡细胞（肝细胞）在活体小鼠中也存在偶联，同时，我们还确定了典型的偶联。 TGF-β 信号传导是外周细胞中细胞生物钟正常耦合所需的途径，在此，我们研究了经典的 TGF-β 信号传导有助于体内肝细胞的细胞间耦合，从而在昼夜节律生理学中发挥重要作用。 ，我们建议研究以下两个目标： 目标 1：表征经典 TGF-β 信号传导在体内肝细胞耦合中的作用 预计外周组织内耦合受损会影响我们将创建规范 TGF-β 信号传导的组织特异性遗传功能丧失小鼠模型，并测试 (i) 时钟基因和时钟控制基因的昼夜节律幅度和相位。目标 2：研究经典 TGF-β 信号传导对肝脏转录组节律作为外周基因表达节律的作用。组织依赖于局部昼夜节律振荡器和节律性系统时间，耦合的扰动可能会影响基因表达的昼夜节律动态，因为对系统输入的反应可能发生改变，我们将使用扰动的规范 TGF-β 来分析小鼠肝脏中的昼夜节律基因表达节律。肝细胞中的信号传导并识别可能受影响的生理途径。