Leukocyte-endothelial cell interaction in aging

描述（由申请人提供）：越来越明显的是，表观遗传学，基因组与环境的相互作用，是我们理解衰老与疾病之间关系的核心。DNA甲基化是控制基因表达的重要表观遗传机制。最近的数据表明，在衰老过程中存在相当大的表观遗传“漂移”，导致包括T细胞在内的许多组织中的相对DNA低甲基化。最初的RO1是为了研究衰老对白细胞趋化因子系统表观遗传控制的影响。我们发现衰老与T细胞促炎趋化因子功能增加有关，这至少部分由DNA甲基化控制。在这个竞争性更新中，我们将确定在免疫系统发育的关键阶段，是否可以通过改变T细胞表观基因组来改善衰老变化。我们假设产前的“表观遗传环境”可以改变T细胞趋化因子受体反应，进而决定晚年对慢性炎症疾病的易感性。特异性目的1将确定产前甲基供体补充饮食在整个生命周期中对小鼠T细胞趋化因子功能的影响。特异性目标2将评估饮食诱导的表观遗传变化对冠状动脉疾病的发生和进展的影响。

DESCRIPTION (provided by applicant): It has become increasingly apparent that epigenetics, where the genome interacts with the environment, is central to our understanding of the relationship between aging and disease. DNA methylation is a key epigenetic mechanism controlling gene expression. Recent data suggest that there is a considerable epigenetic "drift" in aging, resulting in relative DNA hypomethylation in many tissues including T cells. The original RO1 was funded to examine the effect of aging on the epigenetic control of leukocyte chemokine system. We showed that aging is associated with increased T cell pro-inflammatory chemokine function that is at least in part controlled by DNA methylation. In this competing renewal, we will determine if the aging changes can be ameliorated by altering the T cell epigenome during the critical stages of immune system development. We hypothesize that the prenatal 'epigenetic environment' can modify T cell chemokine receptor response that will in turn determine the late-life susceptibility to chronic inflammatory diseases. Specific Aim 1 will determine the effect of a pre-natal methyl-donor supplementation diet on murine T cell chemokine function throughout the life span. Specific Aim 2 will assess the consequence of diet-induced epigenetic changes on the onset and progression of coronary artery disease. PUBLIC HEALTH RELEVANCE: The mechanistic link between aging and chronic diseases in the elderly is poorly understood. Using mouse models, the proposal will examine the effect of a pre-natal methyl-donor supplementation diet on the onset and progression of coronary artery disease in late life.