The role of the circadian clock during Salmonella infection

描述(申请人提供)：进化塑造了所有有机体，使其适应地球绕其轴心自转所产生的昼夜循环。这个系统由一个内部时钟组成，它的分子组成驱动着生物行为、新陈代谢和免疫系统的变化，从而有助于维持身体的动态平衡。已知许多免疫功能遵循昼夜节律，包括几种细胞因子的表达、淋巴细胞的数量和吞噬细胞的活动。此外，各种慢性炎症性疾病，从风湿性关节炎到肥胖症，都与昼夜节律改变有关，而生物钟失调与大多数自身免疫和传染病相关的疾病行为综合征有关。虽然这些研究强调了生物钟在调节免疫功能和炎症方面的重要性，但生物钟在调节宿主对感染的反应中的作用尚不清楚。这项建议的主要目标是通过研究生物钟机制在调节宿主对感染的反应中的作用来开始填补这一关键的知识空白。我们的中心假设是，生物钟机制调节宿主对感染的反应，并有助于决定疾病的严重程度和结局。我们的长期目标是找到控制感染的新途径，并确定治疗和预防策略是否在一天中的特定时间段更有效，为时间药理干预奠定基础。我们计划通过追求以下具体目标来检验我们的假设并实现这一应用的目标：(I)确定生物钟在调节宿主对感染的反应中的作用。(Ii)研究生物钟在感染期间调节抗微生物宿主防御表达的分子机制。

DESCRIPTION (provided by applicant): Evolution has shaped all organisms to adapt to the day-night cycle generated by the rotation of the earth on its axis. This system consists of an internal clock, whose molecular components drive changes in organism behavior, metabolism, and the immune system, thus contributing to maintain body homeostasis. Many immune functions are known to follow a circadian rhythm of activity, including the expression of several cytokines, the number of lymphocytes, and the activity of phagocytic cells. In addition, a variety of chronic inflammatory diseases, from rheumatic arthritis to obesity, have been linked to altered circadian regulation and clock dysregulation is coupled to sickness behavior syndrome associated with most of the autoimmune and infectious diseases. While these studies underline the importance of the circadian clock in regulating immune functions and inflammation, the role of the circadian clock in the regulation of the host response to infection is not known. The primary objective of this proposal is to begin filling this key gap of knowledge by investigating the role of the circadian clock machinery in the regulation of the host response to infection. Our central hypothesis is that the circadian clock machinery regulates the host response to infection, and contributes to determine the severity and outcome of disease. Our long-range goal is to find new avenues to control infection and determine whether therapeutic and preventive strategies may be more effective at specific times of the day, setting up the basis for chronopharmacological intervention. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following Specific Aims: (I) Determine the role of the circadian clock in the regulation of the host response to infection. (II) Investigate the molecular mechanism by which the circadian clock regulates the expression of antimicrobial host defenses during infection.