Gut microbiota and MAIT cell interactions in atherosclerosis

1个项目摘要 心血管疾病（心血管疾病）仍然是美国和全世界死亡的主要原因之一。 3. CVD的潜在风险因素的进展，以及预防干预措施的发展，以减少的情况 4.患者与CVD的治疗的风险和改善。有一种增加了对这个问题的关注 5.肠道微生物对年龄相关CVD的贡献，如人类和小鼠研究中的两个相关变化 在疾病进展的肠道微生物组中。老龄化是治疗性CVD的主要风险因素，以及 7.衰老的过程如炎症和细胞感应可以被肠道微生物组所影响。 8动脉粥样硬化是一种慢性的、低级的炎症反应，其吸引细胞的内在和适应性 9免疫系统进入了药理学clerotic plaque衰老和动脉粥样硬化都与之相连。 与肌肉相关的可变T （MAIT）细胞中的10种改变-本地化的天生类似T细胞的子集 11.最好使用胃肠道受体和识别微衍生维生素B代谢抗原。细胞-- 12个免费的（GF）老鼠在MAIT细胞中是不合格的，以及从传统上增加的老鼠在GF中的殖民化。 13米老鼠在tissue中恢复了MAIT的常见现象，并建议说，肠道微生物是必要的，以完成 MAIT细胞的14个发展。我们的合作者Clement博士最近找到了老年人和患者 15.代谢综合征展示了MAIT的低频率和功能失调，以及这一点 16种现象在CVD患者中有更多的表现。有工具和机器人模型的最新发展 提供了MAIT细胞在疾病中的行动模式和特征的洞察力，但它们在老龄化中的作用 18和动脉粥样硬化仍然被浓缩。Moreover：人类肠道微生物对工业的贡献 19个MAIT细胞仍然是未知的。使用一个带有人类特征样本的Gnotobiotic鼠标模型，我们的原始样本 20个数据显示，老鼠殖民化与一个高MAIT主题的特征有显著的和更高的价值 21个MAIT细胞将老鼠与低MAIT主题相比较。我们现在建议将这一研究扩展到 22使MAIT细胞在动脉粥样硬化发展过程中的频率和功能具有特征（目标1a）;至终止 23 MAIT细胞在使用MR 1固定老鼠（目标1b）中的作用;并测试其在分化中的作用 人类肠道微生物学对MAIT细胞诱导（Aim 2a）和动脉粥样硬化（Aim 2b）。联合小说的作者 MAIT细胞研究中的25个实验工具，如抗加载的MR 1四重奏器，一个基于磁性珠子的 26种Murine MAIT细胞和MAIT细胞deficient MR 1-/- mice的富集方法，具有创新实验 27种方法来调查肠道微生物在动脉粥样硬化中的作用（一、e.，Gnotobiotic atherosclerosis 28个用人类肠道微生物殖民化的机器人，我们打算用它来发现新颖的机制 29 MAIT-Gut微生物学交互模块化发展，将为小说开辟道路 30种微生物中心治疗方法，以预防这种和其他老年相关疾病。

1 PROJECT SUMMARY 2 Cardiovascular disease (CVD) remains the leading cause of death in the United States and worldwide even with 3 advances in the understanding of risk factors for CVD, the development of prevention interventions to reduce 4 the risks, and the improvements in therapy for patients with CVD. There has been an increasing attention in the 5 contribution of the gut microbiota to age-associated CVD, as both human and mouse studies associate changes 6 in the gut microbiome with disease progression. Aging is the dominant risk factor for atherosclerotic CVD, and 7 the process of aging such as inflammation and cellular senescence can be influenced by the gut microbiome. 8 Atherosclerosis is a chronic, low grade inflammatory response that attracts cells of the innate and adaptive 9 immune systems into the atherosclerotic plaque. Both aging and atherosclerosis have been linked with 10 alterations in mucosal-associated invariant T (MAIT) cells ー a subset of innate like T cells that localize 11 preferentially to the gastrointestinal tract and recognize microbial-derived vitamin B metabolite antigens. Germ- 12 free (GF) mice are deficient in MAIT cells, and colonization of feces from conventionally-raised mice into GF 13 mice restores the MAIT frequencies in tissues, suggesting that gut microbes are necessary for the complete 14 development of MAIT cells. Our collaborator Dr. Clement has recently found that elderly subjects and patients 15 with metabolic syndrome exhibit a decreased frequency and functional defects of MAIT and that this 16 phenomenon is more pronounced in patients with CVD. Recent developments of tools and rodent models have 17 provided insight into the mode of action and characterization of MAIT cells in diseases, but their roles in aging 18 and atherosclerosis remains to be elucidated. Moreover, the contribution of human gut microbiota to the induction 19 of MAIT cells are still unknown. Using a gnotobiotic mouse model with human fecal samples, our preliminary 20 data showed that mice colonized with feces from a high MAIT subject had significantly higher abundance of 21 MAIT cells compared to mice with feces from a low MAIT subject. We now propose to extend this study to 22 characterize the frequency and function of MAIT cells during atherosclerosis development (Aim 1a); to elucidate 23 the role of MAIT cells on atherosclerosis using MR1 deficient mice (Aim 1b); and to test the contribution of distinct 24 human gut microbiota to MAIT cell induction (Aim 2a) and atherosclerosis (Aim 2b). Combining novel 25 experimental tools in studying MAIT cell, such as antigen-loaded MR1 tetramers, a magnetic bead-based 26 enrichment method of murine MAIT cells, and MAIT cell-deficient MR1-/- mice, with innovative experimental 27 approaches to investigate the role of the gut microbiota on atherosclerosis (i.e., gnotobiotic atherosclerosis- 28 prone mice colonized with human gut microbiota), we anticipate to discover novel mechanisms by which the 29 MAIT – gut microbiota interactions modulate development of atherosclerosis, will pave the way for novel 30 microbiome-center therapies to prevent this and potentially other aging-associated diseases.