Dietary impact on blood-brain barrier tight junctions

 描述(申请人提供)：血脑屏障(BBB)的一个重要属性是存在于相邻内皮细胞之间的紧密连接(TJ)的独特复合体，它阻碍细胞旁扩散并帮助维持脑内平衡。大量证据表明，BBB-TJ功能障碍是中枢神经系统(CNS)疾病的主要因素。虽然越来越明显的是，促炎的高脂肪“西方”饮食有助于中枢神经系统疾病，但这种饮食对BBB TJ的影响还没有完全阐明。同样，omega-3(ω3)多不饱和脂肪酸(PUFA)对血脑屏障TJ调节的潜在益处也尚不清楚。这项检查的目的是阐明饮食脂肪对BBB TJ完整性和蛋白质调节的影响，分别与炎症贡献有关。这项研究分为两个目的：1)确定西方饮食与omega-3饮食对BBB、TJ完整性和蛋白质随时间的调节的影响。在14周和28周的饮食治疗(C57BL/6小鼠)中，将评估与高脂和低脂饮食相对应的血脑屏障TJ蛋白调节(微血管分离)和细胞旁完整性(渗透性标记物)，无论是否使用主要的ω-3多不饱和脂肪酸(EPA和DHA)。支持性评估将评估主要的饮食变量、炎症成分和PPARγ的改变。2)确定西方饮食和omega-3饮食对BBB TJ完整性和应对急性炎症挑战的蛋白质调节的影响。在这里，14周的饮食治疗将通过脂多糖(LPS)来应对急性炎症挑战，随后是AIM-1中确定的评估集。在注射脂多糖后的关键炎症时间点评估BBB TJ将允许描绘BBB TJ的易感性和恢复力 饮食治疗。这项探索性研究将为膳食脂肪对BBB TJ的健康和弹性的影响提供新的见解，以及对炎症影响的更好理解。此外，它将作为未来与血脑屏障相关的考试的基础 监管和疾病后果。这项研究的目的是处理国家卫生研究所的优先事项，分别是国家神经疾病和中风研究所(NINDS)、国家老龄研究所(NIA)、国家补充和替代医学中心(NCCAM)和膳食补充剂办公室(Ods)。

 DESCRIPTION (provided by applicant): A critical property of the blood-brain barrier (BBB) is the unique complex of tight junctions (TJs) that exist between adjacent endothelial cells, which impede paracellular diffusion and help maintain brain homeostasis. Numerous lines of evidence implicate BBB TJ dysfunction as a primary contributor to central nervous system (CNS) disease. While it has become increasingly evident that pro-inflammatory high-fat "Western" diets contribute to CNS disease, the impact of such diets on the BBB TJs has not been fully elucidated. Likewise, the potential benefit of omega-3 (ω3) polyunsaturated fatty acids (PUFAs) on BBB TJ regulation also remains unclear. The goal of this examination is to elucidate the effects of dietary fats on BBB TJ integrity and protein regulation, respective to inflammatory contributions. This study is divided into two aims: 1) Determine the effect of Western vs. omega-3 based diets on BBB TJ integrity and protein regulation over time. Evaluations of BBB TJ protein regulation (microvascular isolate) and paracellular integrity (permeability marker) corresponding with high and low fat diets, both with and without primary ω-3 PUFAs (EPA and DHA), will be assessed over 14- and 28-weeks of dietary treatment (C57BL/6 mice). Supportive evaluations will assess primary dietary variables, inflammatory components, and PPARγ alterations. 2) Determine the effect of Western vs. omega-3 based diets on BBB TJ integrity and protein regulation against an acute inflammatory challenge. Herein, 14-week dietary treatments will be run against an acute inflammatory challenge via lipopolysaccharide (LPS), followed by evaluation sets identified in aim-1. Assessing BBB TJs at key inflammatory time-points, post-LPS injection, will allow for the delineation of BBB TJ susceptibility and resilience respective to dietary treatments. This exploratory study will provide novel insight into the impact of dietary fas on the health and resilience of the BBB TJs, as well as a greater understanding of inflammatory influences. Additionally, it will serve as the foundation for future examinations respective to BBB regulation and disease outcomes. The aims of this study address priorities of National Institutes of Health, respective to the National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Aging (NIA), National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS).