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个项目摘要 2心血管疾病（CVD）仍然是美国和全球的主要死亡原因 3了解CVD风险因素的进步，预防干预措施的发展 4风险和CVD患者的治疗改善。在 5肠道菌群对与年龄相关的CVD的贡献，因为人类和小鼠研究都会改变 6在肠道微生物组中，疾病进展。衰老是动脉粥样硬化CVD的主要危险因素，并且 7感染和细胞感染等衰老过程可能受肠道微生物组的影响。 8动脉粥样硬化是一种慢性，低年级的炎症反应，吸引了先天和适应性的细胞 9个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粘膜相关不变t（MAIT）细胞的10个改变 - 先天性的T细胞的子集 11优先地对胃肠道，并识别微生物衍生的维生素B代谢产物抗原。细菌 12只游离（GF）小鼠缺乏Mait细胞，并从传统饲养的小鼠的粪便定植到GF中 13只小鼠恢复组织中的Mait频率，这表明肠道微生物是完整的 14 MAIT细胞的发展。我们的合作者克莱门特博士最近发现，古老的受试者和患者 15与代谢综合征表现出频率和功能性缺陷的降低，这是 16现象在CVD患者中更为明显。工具和啮齿动物模型的最新发展具有 17提供了有关疾病中Mait细胞的作用方式和表征的洞察力，但它们在衰老中的作用 18和动脉粥样硬化尚待阐明。此外，人类肠道菌群对诱导的贡献 19个Mait细胞仍然未知。使用人类粪便样品使用gnotobiotic小鼠模型，我们的初步 20个数据表明，用高MAIT受试者定居的粪便定居的小鼠的丰度明显更高与低MAIT受试者的粪便相比，有21个Mait细胞。我们现在建议将这项研究扩展到 22在动脉粥样硬化发育过程中表征MAIT细胞的频率和功能（AIM 1A）；阐明 23使用MR1缺乏小鼠（AIM 1B），MAIT细胞对动脉粥样硬化的作用；并测试独特的贡献 24人肠道菌群对MAIT细胞诱导（AIM 2A）和动脉粥样硬化（AIM 2B）。结合小说 25个研究MAIT细胞的实验工具，例如抗原负载的MR1四聚体，一种基于磁珠的基于磁珠 26鼠Mait细胞的富集方法，以及具有创新的实验性的MAIT细胞缺陷MR1 - / - 小鼠 27研究肠道菌群对动脉粥样硬化的作用的方法（即gnotobirotic动脉粥样硬化 - 28俯卧的小鼠用人肠道菌群定居），我们预计会发现新的机制 29 MAIT - 肠道菌群相互作用调节动脉粥样硬化的发展，将为新颖的道路铺平道路 30微生物组中心疗法可防止这种疾病和可能与其他衰老相关的疾病。