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Role of purinergic receptor P2X7 in the differentiation and function of iNKT cell subsets

嘌呤能受体P2X7在iNKT细胞亚群分化和功能中的作用

基本信息

批准号：
10090983
负责人：
Meng Zhao
金额：
$ 34.96万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
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：
2021-02-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10090983
关键词：
Ablation Affect Agonist Antigens Autoimmune Diseases Autophagocytosis Bacterial Infections Bioenergetics Biological Assay CD8-Positive T-Lymphocytes Cell physiology Cells Cellular Metabolic Process Centers of Research Excellence Cytokine Signaling Cytotoxic T-Lymphocytes Development Enzymes Flow Cytometry Gene Expression Genetic Glucose Goals Grant Homeostasis IL4 gene Image Inflammatory Interleukin-4 Ligands Lipids Mainstreaming Maintenance Mediating Memory Metabolic Metabolic Pathway Metabolism Mitochondria Nutrient Oklahoma Organ Organ Culture Techniques Oxidative Phosphorylation Pathologic Pathway interactions Play Population Process Production Purinoceptor Radiolabeled Research Respiration Role Signal Transduction Specificity Stream System T cell differentiation T cell regulation T cell therapy T memory cell T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TCR Activation Testing Thymus Gland Tracer base calcium uniporter design exhaustion extracellular glucose metabolism human disease inhibitor/antagonist insight metabolic phenotype new therapeutic target novel novel therapeutics oxidation programs sensor targeted treatment tumor microenvironment

项目摘要

Metabolic reprogramming supports the differentiation, expansion and functional maturation of effector and memory T cells. It is also contributing to the de-regulation of T cell functions, such as T cell exhaustion in the tumor microenvironment, or break of tolerance in autoimmune diseases. Understanding how distinct metabolic programs are regulated to facilitate lineage specific development and function will provide important insight for designing new therapeutics targeting T cell metabolism. iNKT cells are a group of innate-like T cells, playing important roles in many pathological conditions. iNKT cell differentiation into mature functional subsets NKT1, 2 and 17 in the thymus represents an alternative paradigm of T cell development. In our preliminary study, we have identified distinctive metabolic features of iNKT cell subsets, and the purinergic receptor P2X7 as a new regulator for iNKT cell differentiation. The overall goal of this study is to define the mechanism how P2X7 modulates subset specialization and functional maturation. In Aim 1, we will determine the role of P2X7 as an ATP gated Ca2+ channel to promote optimal Ca2+ signals during iNKT cell differentiation. We will explore the connections between P2X7 and TCR activation, as well as Ca2+ as an important co-factor for mitochondria respiration. In Aim 2, we will define the role of P2X7 as a metabolic regulator during iNKT cell differentiation and activation. We will test if and how P2X7 regulates glucose metabolism, and if the energy sensor AMPK acts down stream of P2X7 activation. The immediate contribution of this study is to reveal novel metabolic components/processes, such as extracellular ATP (eATP, ligands for P2X7), Ca2+ signal, and mitochondria, which can specifically modulate iNKT subsets differentiation and effector functions. The support from a COBRE grant will enable us to take a critical step towards our long-term goal, targeting innate-like T cell metabolism to treat human diseases.

代谢重编程支持效应子和受体的分化、扩增和功能成熟。记忆T细胞它还有助于T细胞功能的失调，例如在免疫缺陷病毒中的T细胞耗竭。肿瘤微环境或自身免疫性疾病中耐受性的破坏。了解不同的新陈代谢调节程序以促进谱系特异性发育和功能将为以下方面提供重要的见解：设计针对T细胞代谢的新疗法。iNKT细胞是一组先天性T细胞，在许多病理条件下的重要作用。iNKT细胞分化为成熟功能亚群NKT 1，2 和17代表了T细胞发育的另一种模式。在初步研究中，我们已经确定了iNKT细胞亚群的独特代谢特征，嘌呤能受体P2 X7是一种新的 iNKT细胞分化的调节剂。本研究的总体目标是确定P2 X7 调节子集特化和功能成熟。在目标1中，我们将确定P2 X7作为 ATP门控Ca 2+通道促进iNKT细胞分化期间的最佳Ca 2+信号。我们将探讨 P2 X7和TCR激活之间的联系，以及Ca 2+作为线粒体的重要辅助因子呼吸在目标2中，我们将定义P2 X7在iNKT细胞分化过程中作为代谢调节剂的作用， activation.我们将测试P2 X7是否以及如何调节葡萄糖代谢，以及能量传感器AMPK是否起作用。 P2 X7激活的下游。这项研究的直接贡献是揭示了新的代谢组分/过程，例如细胞外ATP（eATP，P2 X7的配体）、Ca 2+信号和线粒体，其可特异性调节iNKT亚群分化和效应子功能。来自眼镜蛇的支持这笔赠款将使我们能够朝着我们的长期目标迈出关键一步，目标是先天性T细胞代谢来治疗人类疾病