Dissecting the role of CD8+ T cells in atherosclerosis

剖析 CD8 T 细胞在动脉粥样硬化中的作用

基本信息

批准号：
10034860
负责人：
Chiara Giannarelli
金额：
$ 65.41万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10034860
关键词：
Acute Address Affect Apolipoprotein E Arterial Fatty Streak Atherosclerosis Automobile Driving Biological Models CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cardiovascular system Carotid Artery Plaques Carotid Endarterectomy Cells Cellular biology Clinical Complement Coronary Arteriosclerosis Coronary heart disease Data Disease Disease Progression Disease model Down-Regulation Epitopes Event Frequencies Future Gene Expression Gene Proteins Genes Genetic Polymorphism Genetic Transcription Goals Granzyme High Fat Diet Histologic Human ID2 gene Immune Immunotherapy Knowledge Link Mediating Memory Molecular Molecular Target Mus Myocardial Nature Organ Donor Outcome Pathologic Pathology Patients Phenotype Proteins Public Health Publishing Regulation Rest Role Rupture Signal Pathway Signaling Protein Stroke Surgical margins T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Variant Work cell type cytotoxic cytotoxicity design disability effector T cell exhaust exhaustion experience genome-wide analysis healing human data in vivo indexing innovation mortality prevent programmed cell death protein 1 residence risk variant single cell analysis single-cell RNA sequencing stroke patient transcription factor transcriptome

项目摘要

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ACVD) is the leading cause of mortality and disability worldwide, even in optimally treated patients. While the impact of many immune cell types on atherosclerosis is well- established, the contribution of CD8+ T cells to the disease pathology remains to be further elucidated. In previous work using unbiased single-cell (sc) analyses to study the immune composition of human atherosclerotic plaques we found new dysregulations tissue resident memory (TRM) CD8+ T cells associated with clinical CV outcomes. CD8+ T cell infiltrates have been described in both early and advanced human atherosclerotic plaques and their cytotoxic effector functions contribute to plaque progression in mice. However, information on how CD8+ T cells contribute to atherosclerotic plaque vulnerability and cardiovascular (CV) events is limited and remains to be fully understood. In preliminary sc studies, we identified the transcriptional regulator Zeb 2 as a top candidate master regulator of plaque CD8+ T cell proatherogenic alterations. We hypothesize that Zeb2 is a key driver of the activation and cytotoxicity of effector TRM CD8+ T cells in atherosclerotic plaques and that these alterations contribute to disease progression and plaque vulnerability. We also contend that its downregulation is implicated in the reprogramming of PD-1+ TRM CD8+ T cells found in plaques of patients with recent stroke. We propose two independent aims to study the role of Zeb2 in plaque vulnerability and CV events. In Aim 1, we will dissect the Zeb2-mediated activation of plaque TRM CD8+ T cells and determine their association with plaque vulnerability at pathology. In this Aim we will also determine the effect of Zeb2 deficiency selectively in activated TRM CD8+ on atherosclerosis in mice. In Aim 2, we will identify how Zeb2 mediates TRM CD8+ T cell dysregulations of adverse CV outcomes and determine how Zeb2 downregulation in all CD8+ T cell affect their exhaustion reprogramming and whether these alterations contribute to plaque size and vulnerability in vivo. These studies will address important gaps in knowledge in CD8+ T cell biology in atherosclerosis, and will tackle previously unappreciated cellular and molecular mechanisms associated with plaque rupture/erosion that may contribute to clinical CV outcomes. We foresee that this information may help guide the future design of precise, molecularly targeted immunotherapies to prevent CV outcomes in patients with carotid and coronary disease.

项目摘要动脉粥样硬化心血管疾病（ACVD）是全球死亡率和残疾的主要原因，甚至在经过最佳治疗的患者中。虽然许多免疫细胞类型对动脉粥样硬化的影响良好建立的CD8+ T细胞对疾病病理学的贡献尚待进一步阐明。在先前使用无偏单细胞（SC）分析研究人类免疫组成的工作动脉粥样硬化斑块我们发现新的失调组织驻留记忆（TRM）CD8+ T细胞相关与临床简历结果。 CD8+ T细胞浸润已在早期和晚期人类中描述动脉粥样硬化斑块及其细胞毒性效应子功能有助于小鼠的斑块进展。但是，有关CD8+ T细胞如何促进动脉粥样硬化斑块脆弱性和心血管的信息（简历）事件是有限的，尚待充分理解。在初步研究中，我们确定了转录调节器ZEB 2作为牙菌斑CD8+ T细胞质源性的顶级候选主调节器改变。我们假设Zeb2是效应子TRM CD8+ T的激活和细胞毒性的关键驱动力动脉粥样硬化斑块中的细胞，这些改变有助于疾病进展和斑块脆弱性。我们还认为，其下调与PD-1+ TRM CD8+ T的重编程有关细胞在最近中风的患者斑块中发现。我们提出了两个独立的目标，以研究斑块漏洞和简历事件中的Zeb2。在AIM 1中，我们将剖析Zeb2介导的斑块激活 TRM CD8+ T细胞并确定它们与病理学上斑块脆弱性的关联。在这个目标中，我们也将确定Zeb2缺乏症在活化的TRM CD8+中对小鼠动脉粥样硬化的影响。在AIM 2中，我们将确定Zeb2如何介导不良CV结果的TRM CD8+ T细胞失调并确定 Zeb2在所有CD8+ T细胞中如何下调如何影响其耗尽的重编程以及这些是否是否变化导致体内斑块大小和脆弱性。这些研究将解决重要的差距关于动脉粥样硬化中CD8+ T细胞生物学的知识，并将处理以前未欣赏的细胞和与斑块破裂/侵蚀相关的分子机制，可能导致临床CV结果。我们预见，此信息可能有助于指导未来的精确设计，分子针对性免疫疗法可预防颈动脉和冠状动脉疾病患者的简历结局。