Biology of the NK cell cytolytic activity rhythm

NK 细胞溶细胞活性节律的生物学

基本信息

批准号：
7895704
负责人：
DIPAK KUMAR SARKAR
金额：
$ 41.33万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

Circadian and daily rhythms regulate many aspects of physiology and behavior. Although a growing number of studies suggest that circadian disruptions may render organisms more susceptible to infection and cancer, the molecular links between the circadian system and the immune system are largely unknown. Natural killer (NK) cell cytolytic activity has been shown to follow a daily rhythm, which is under a circadian control. NK cells participate in the immune response against viral infections and cancer. Employing the rat animal model, this proposal determines the mechanisms by which the circadian rhythm of splenic NK cell cytolytic function is regulated. It tests the hypothesis that splenic NK cells are provided with molecular clocks that orchestrate the rhythmic expression of cytolytic factors that drive the circadian rhythm of NK cell cytolytic function. The hypothalamic suprachaismatic nucleus, which is itsetf, entrained by photic input, coordinates the expression of clock regulatory genes by altering the sympathetic outflow to the splenic NK cells. The proposed research uses magnetic separation techniques to isolate the NK cell population from the spleen to determine the changes in cytotoxic factors, cytokines and clock genes in these cells; employs gene knockdown techniques in NK cells to study the influence Of clock genes on cytolytic function; analyzes the circadian variations in the clearance of NK-sensitive tumor cells; determines the susceptibility of NK cell function to jet lag, a common circadian disruption, and uses pharmacological tools to investigate the signaling mechanism critically involved in resetting the circadian clock in splenic and clonal NK cells. The proposed series of studies should enhance our knowledge of the physiological mechanisms orchestrating NK cell circadian function.

昼夜节律和日常节律调节生理和行为的许多方面。尽管越来越多的研究表明昼夜节律紊乱可能使生物体更容易受到感染和癌症，但昼夜节律系统和免疫系统之间的分子联系在很大程度上尚不清楚。自然杀伤 (NK) 细胞的溶细胞活性已被证明遵循每日节律，受昼夜节律控制。 NK 细胞参与针对病毒感染和癌症的免疫反应。该提案采用大鼠动物模型，确定了脾脏 NK 细胞溶细胞功能昼夜节律的调节机制。它测试了这样的假设：脾脏 NK 细胞具有分子时钟，可以协调细胞溶解因子的节律表达，从而驱动 NK 细胞细胞溶解功能的昼夜节律。下丘脑上核本身受到光输入的影响，通过改变交感神经向脾脏 NK 细胞的流出来协调时钟调节基因的表达。拟议的研究利用磁力分离技术从脾脏中分离出 NK 细胞群，以确定这些细胞中细胞毒性因子、细胞因子和时钟基因的变化；在NK细胞中采用基因敲除技术来研究时钟基因对溶细胞功能的影响；分析 NK 敏感肿瘤细胞清除的昼夜节律变化；确定 NK 细胞功能对时差反应（一种常见的昼夜节律紊乱）的敏感性，并使用药理学工具研究与重置脾脏和克隆 NK 细胞的生物钟至关重要的信号传导机制。拟议的一系列研究应增强我们对协调 NK 细胞昼夜节律功能的生理机制的了解。