Circadian clocks of the adrenal medulla

细胞生物钟网络调节24小时的生理和行为节律，使生物体适应地球绕其轴旋转所带来的外部环境的反复变化。在分子水平上，一组时钟基因组织在一个互锁的转录-翻译反馈环系统中，驱动组织特异性转录程序的节律性激活，以协调沿着24小时的细胞生理。下丘脑-垂体-肾上腺（HPA）应激轴的活动受到严格的昼夜节律控制，在活动期开始时具有峰值活动，即在人类中的早晨和在夜间啮齿动物中的晚上。我们以前已经表明，生物钟调节肾上腺糖皮质激素（GC）的分泌在基线条件下，以应对压力。小鼠移植实验进一步表明，肾上腺时钟门控GC响应传入刺激的敏感性。遗传实验进一步表明，肾上腺皮质时钟功能是昼夜节律和应激诱导的GC释放，在这种情况下，肾上腺髓质时钟的作用。为了测试这一点，我们将在这个项目中产生特定的肾上腺髓质中的时钟功能中断的小鼠，并在这些动物中表征昼夜节律和应激相关的HPA轴活动和组织时钟调节。我们将进一步解剖肾上腺髓质和GC产生皮质细胞之间的通信途径的类固醇机制的昼夜节律门控使用体内和体外的方法。

A network of cellular circadian clocks regulates 24-h rhythms of physiology and behavior, adapting the organism to recurring changes in the external environment brought about by the Earth's rotation around its axis. At the molecular level, a set of clock genes organized in a system of interlocked transcription-translational feedback loops drive rhythmic activation of tissue-specific transcriptional programs to coordinate cellular physiology along the 24-h day. Activity of the hypothalamus-pituitary-adrenal (HPA) stress axis is under strict circadian control with peak activity at the beginning of the active period, i.e. the morning in man and the evening in nocturnal rodents. We have previously shown that circadian clocks regulate secretion of glucocorticoids (GCs) from the adrenal under baseline conditions in response to stress. Transplantation experiments in mice further suggested that adrenal clocks gate the sensitivity of GC responses to incoming stimuli. Genetic experiments further suggested that adrenocortical clock function is dispensable for circadian and stress-induced GC release, pointing at a role of the adrenomedullary clock in this context. To test this, we will in this project generate mice with specific disruption of clock function in the adrenal medulla and characterize circadian and stress-related HPA axis activity and tissue clock regulation in these animals. We will further dissect the communication pathways between adrenal medulla and GC-producing cortical cells underlying the circadian gating of the steroidogenic machinery using both in-vivo and ex-vivo approaches.