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，在视交叉上核的昼夜振荡细胞之间的耦合是需要凝聚力，强大的和高振幅的节奏。然而，外围细胞时钟之间是否也存在耦合存在争议，可能的机制也是未知的。最近，Schibler实验室能够明确地表明，外周振荡细胞（肝细胞）也在活体小鼠中偶联。与此同时，我们已经确定了典型的TGF-β信号传导作为外周细胞中细胞生物钟正常偶联所需的途径。在这里，我们假设经典的TGF-β信号传导有助于体内肝细胞的细胞间偶联，从而在昼夜节律生理学中发挥重要作用。为了验证这一假设，我们提出研究以下两个目标：目标1：表征典型的TGF-β信号传导在体内肝细胞偶联中的作用，预测外周组织内偶联的损伤会影响内聚性、振幅、相位以及对zeitgebers的响应。我们将创建典型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）生物钟基因和生物钟控制基因的昼夜节律幅度和相位是否受到影响;（ii）进食逆转时相移的动力学是否改变。目标二：由于外周组织中的基因表达节律取决于局部昼夜节律振荡器和节律性系统授时因子两者，耦合的扰动可能会影响基因表达的昼夜节律动力学，这是由于对系统输入的潜在改变的响应。我们将分析小鼠肝脏中的昼夜节律基因表达节律，肝细胞中的典型TGF-β信号转导受到干扰，并确定可能受影响的生理途径。