Gut microbiota and MAIT cell interactions in atherosclerosis

肠道微生物群和 MAIT 细胞在动脉粥样硬化中的相互作用

基本信息

批准号：
10429936
负责人：
Kazuyuki Kasahara
金额：
$ 18.77万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10429936
关键词：
Affect Age Aging Antibodies Antigens Arterial Fatty Streak Atherosclerosis Attention Biological Response Modifiers Cardiovascular Diseases Cardiovascular system Cause of Death Cell Aging Cell Communication Cell Shape Cell physiology Cells Cellular Structures Chronic Communities Data Defect Development Diabetes Mellitus Disease Disease Progression Elderly Equilibrium Event Exhibits Feces Frequencies Functional disorder Gastrointestinal tract structure Genetic Germ Germ-Free Gnotobiotic Goals Gut Mucosa Health Human Immune Immune system Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 beta Intestines LDL Cholesterol Lipoproteins Lesion Link Lipids Metabolic syndrome Metabolism Methods Microbe Mucous Membrane Mus Obesity Patients Persons Phenotype Play Population Prevalence Prevention Process Proprotein Convertases Recombinant adeno-associated virus (rAAV)Risk Risk Factors Rodent Model Role Sampling Severities Structure Subtilisins T-Lymphocyte Testing Time Tissues United States Vitamin B Complex age related base cardiovascular risk factor cell age chronic inflammatory disease cytokine design dysbiosis fecal microbiota gut microbes gut microbiome gut microbiota hypercholesterolemia immunosenescence innovation insight magnetic beads microbial microbiome microbiota mouse model novel novel strategies older patient prevent preventive intervention systemic inflammatory response tool tool development

项目摘要

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.

1 项目概要 2 即使在美国和世界范围内，心血管疾病 (CVD) 仍然是导致死亡的主要原因 3. 对CVD危险因素的认识取得进展，制定预防干预措施以减少 4 CVD患者的风险和治疗方法的改进越来越受到人们的关注。 5 肠道微生物群对与年龄相关的 CVD 的贡献，人类和小鼠研究均将变化联系起来 6 肠道微生物群中的疾病进展衰老是动脉粥样硬化 CVD 的主要危险因素，并且 7 炎症和细胞衰老等衰老过程可能受到肠道微生物组的影响。 8 动脉粥样硬化是一种慢性、低度炎症反应，会吸引先天性和适应性细胞 9 免疫系统进入动脉粥样硬化斑块衰老和动脉粥样硬化都与此相关。粘膜相关不变 T (MAIT) 细胞的 10 种改变——先天性 T 细胞的一个子集，可定位 11 优先进入胃肠道并识别微生物衍生的维生素 B 代谢抗原。 12 只游离 (GF) 小鼠缺乏 MAIT 细胞，传统饲养小鼠的粪便定植到 GF 中 13 只小鼠恢复了组织中的 MAIT 频率，这表明肠道微生物对于完整的 14 MAIT 细胞的开发我们的合作者 Clement 博士最近发现老年受试者和患者。 15 患有代谢症状综合征的 MAIT 频率降低且功能缺陷，这 16 这一现象在 CVD 患者中更为明显。 17 深入了解了 MAIT 细胞在疾病中的作用模式和特征，以及它们在衰老中的作用 18 和动脉粥样硬化还有待阐明。此外，人类肠道微生物群对诱导的贡献仍有待阐明。 19 的 MAIT 细胞仍然未知，我们使用带有人类粪便样本的无菌小鼠模型进行了初步研究。 20 数据显示，被高 MAIT 受试者粪便定植的小鼠具有显着更高的丰度 21 MAIT 细胞与低 MAIT 受试者粪便的小鼠进行比较我们现在建议将这项研究扩展到 22 描述动脉粥样硬化发展过程中 MAIT 细胞的频率和功能（目标 1a）； 23 使用 MR1 缺陷小鼠观察 MAIT 细胞对动脉粥样硬化的作用（目标 1b），并测试不同细胞的贡献； 24 人类肠道微生物群对 MAIT 细胞的诱导（目标 2a）和动脉粥样硬化（目标 2b）的结合。研究 MAIT 细胞的 25 种实验工具，例如负载抗原的 MR1 四聚体、基于磁珠的 26. 小鼠MAIT细胞的富集方法，以及MAIT细胞缺陷的MR1-/-小鼠，具有创新的实验 27 种方法研究肠道微生物群对动脉粥样硬化的作用（即，抗生素动脉粥样硬化- 28 只易受感染的小鼠被人类肠道微生物群定植），我们预计会发现新的机制，通过这些机制 29 MAIT——肠道微生物群相互作用调节动脉粥样硬化的发展，将为新的研究铺平道路 30 种以微生物组为中心的疗法可预防这种疾病以及其他潜在的与衰老相关的疾病。