A role of DPP4 in T cell trafficking and vascular inflammation

DPP4 在 T 细胞运输和血管炎症中的作用

• 批准号: 9883574
• 负责人: Jixin Zhong
• 金额: $ 2.06万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-05 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883574
• 关键词: Address; Adipose tissue; Adoptive Transfer; Affect; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; Binding; Biology; Blood; Bone Marrow; CD44 gene; Cardiovascular Diseases; Cause of Death; Cell Communication; Cell physiology; Cells; Chronic; Cytoskeleton; Dendritic Cells; Detection; Developed Countries; Diabetes Mellitus; Dipeptidyl Peptidases; Disease; Dyslipidemias; Endocytosis; Endosomes; Event; Flow Cytometry; Functional disorder; Gastric Inhibitory Polypeptide; Genes; Glucose; Heart Diseases; Hematopoietic; Human; Image; Inflammation; Inflammatory; Insulin; Interleukin-6; Knock-in; Knock-out; Knockout Mice; Knowledge; LDL Cholesterol Lipoproteins; Lead; Ligand Binding; Ligands; Mediating; Microtubules; Morphology; Mus; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Process; Reporter; Reporting; Role; SELL gene; Shapes; Signal Transduction; Subfamily lentivirinae; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Tumor-infiltrating immune cells; United States; Vascular Diseases; Work; adenosine deaminase; cardiometabolism; cell motility; chemokine; disability; feeding; glucagon-like peptide 1; improved; in vivo; inflammatory marker; inhibitor/antagonist; insight; lymphoid organ; migration; neglect; novel; novel therapeutics; overexpression; patient subsets; protective effect; reconstitution; synaptogenesis; trafficking; transcriptomics; two photon microscopy; ubiquitin-protein ligase; vascular inflammation

ABSTRACT Atherosclerosis is the main cause of death and disability in industrialized nations, including the United States. Despite of significant advances in recent years, the treatment of cardiovascular disease is unsatisfied partly due to the limitations in our understanding of the atherosclerosis pathophysiology. Growing evidence indicates that atherosclerosis is a chronic inflammatory process that accelerates in the context of dyslipidemia. Gaining new knowledge on inflammatory mechanisms in this disorder is a very important endeavor as this could lead to new therapies for the treatment of this condition. Both our previous work and preliminary study indicate that dipeptidyl peptidase-4 (DPP4) plays a critical role in regulating T cell-mediated inflammation in cardiometabolic disease such as atherosclerosis and diabetes. Single cell transcriptomic analysis indicates that DPP4 was significantly upregulated in major T cell subsets from patients with atherosclerosis. Ldlr-/- chimeric mice with Dpp4-/- bone marrow showed reduced atherosclerotic plaque burden and less T cell infiltration in the plaque. Subsequent gene array and T cell functional studies suggest microtubule-associated E3 ubiquitin ligase midline-1 (Mid1) mediates DPP4-induced T cell activation and migration. Both Dpp4-/- T cells and Mid1-/- T cells showed reduced migratory activity, while lentivirus-mediated over-expression of Mid1 restored the migratory ability of Dpp4-/- T cells. Our overall hypothesis is that DPP4 activation by ligand binding regulates microtubule-mediated cytoskeleton rearrangement and endocytosis via Mid1-dependent mechanisms, resulting in enhanced T cell migration to aortic plaque, a key event in the pathogenesis of atherosclerosis. In this application, we will test the involvement of DPP4 in T cell inflammation and human atherosclerosis (aim 1). We will also use several unique animal models (including hDpp4KI, Mid1-/-, Dpp4-/-, Dpp4-/-/Mid1-/- double knockout, and multiple reporter mice) and state-of-the-art technologies (such as imaging flow cytometry and intravital 2- photon microscopy) to dissect the role of DPP4-Mid1 axis in regulating T cell activation and migration to atherosclerotic plaque (aim 2). The in vivo effects of DPP4 and Mid1 on atherosclerosis progression will be investigated in aim 3. This proposal not only addresses important knowledge gaps in DPP4 biology, but would also identify novel contributors to human atherosclerosis and other disease states where inflammation plays a critical role.

抽象的 动脉粥样硬化是包括美国在内的工业化国家死亡和残疾的主要原因。 尽管近年来取得了显着进展，但心血管疾病的治疗仍不尽如人意。 由于我们对动脉粥样硬化病理生理学的理解有限。越来越多的证据表明 动脉粥样硬化是一种慢性炎症过程，在血脂异常的情况下会加速。获得 关于这种疾病炎症机制的新知识是一项非常重要的努力，因为这可能会导致 治疗这种疾病的新疗法。我们之前的工作和初步研究表明 二肽基肽酶-4 (DPP4) 在调节心脏代谢中 T 细胞介导的炎症中发挥着关键作用 动脉粥样硬化和糖尿病等疾病。单细胞转录组分析表明 DPP4 动脉粥样硬化患者的主要 T 细胞亚群显着上调。 Ldlr-/-嵌合小鼠 Dpp4-/- 骨髓显示动脉粥样硬化斑块负荷减少，斑块中 T 细胞浸润减少。 随后的基因阵列和 T 细胞功能研究表明微管相关的 E3 泛素连接酶 midline-1 (Mid1) 介导 DPP4 诱导的 T 细胞激活和迁移。 Dpp4-/- T 细胞和 Mid1-/- T 细胞 显示迁移活性降低，而慢病毒介导的 Mid1 过度表达恢复了迁移活性 Dpp4-/- T 细胞的能力。我们的总体假设是配体结合调节 DPP4 激活 通过 Mid1 依赖性机制微管介导的细胞骨架重排和内吞作用，从而产生 增强 T 细胞向主动脉斑块的迁移，这是动脉粥样硬化发病机制中的一个关键事件。在这个 应用程序中，我们将测试 DPP4 在 T 细胞炎症和人类动脉粥样硬化中的参与（目标 1）。我们 还将使用几种独特的动物模型（包括 hDpp4KI、Mid1-/-、Dpp4-/-、Dpp4-/-/Mid1-/- 双敲除、 和多个报告小鼠）和最先进的技术（例如成像流式细胞术和活体 2- 光子显微镜）剖析 DPP4-Mid1 轴在调节 T 细胞活化和迁移中的作用 动脉粥样硬化斑块（目标 2）。 DPP4 和 Mid1 对动脉粥样硬化进展的体内影响将是 在目标 3 中进行了研究。该提案不仅解决了 DPP4 生物学中的重要知识差距，而且将 还确定了人类动脉粥样硬化和炎症发挥作用的其他疾病状态的新因素 关键作用。

项目成果

Glucagon-Like Peptide-1 Receptor Regulates Macrophage Migration in Monosodium Urate-Induced Peritoneal Inflammation.

胰高血糖素样肽 1 受体调节尿酸钠诱导的腹膜炎症中巨噬细胞的迁移。

• 发表时间: 2022
• 作者: Chen, Jun;Mei, Aihua;Liu, Xinxin;Braunstein, Zachary;Wei, Yingying;Wang, Biao;Duan, Lihua;Rao, Xiaoquan;Rajagopalan, Sanjay;Dong, Lingli;Zhong, Jixin
• 通讯作者: Zhong, Jixin