The role of selenoprotein I in phospholipidethanolamine dependent mechanisms that regulate T cell activation

硒蛋白 I 在调节 T 细胞活化的磷脂乙醇胺依赖性机制中的作用

• 批准号: 10397133
• 负责人: Peter R Hoffmann
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397133
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Affinity; Aging; Amino Acid Transporter; Amino Acids; Anabolism; Antigens; B-Lymphocytes; Biological; Biological Assay; Biology; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell Line; Cell division; Cell membrane; Cell physiology; Cells; Cellular Membrane; Chronic; Clonal Expansion; Complex; Cytokinesis; Data; Diet; Dietary Selenium; Disease; Endoplasmic Reticulum; Enzymes; Equilibrium; Event; Exhibits; Family; Goals; Health; Human; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunology; Immunosuppression; Impairment; Individual; Intake; Interleukin 2 Receptor; Lead; Malignant Neoplasms; Measures; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Proteins; Memory; Messenger RNA; Micronutrients; Modeling; Murine Acquired Immunodeficiency Syndrome; Mus; Mutation; Pathway interactions; Phenotype; Phosphatidylethanolamine; Phospholipids; Play; Process; Production; Property; Proteins; Publishing; Rattus; Receptor Signaling; Research; Role; Selenium; Selenocysteine; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; Supplementation; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Trace Elements; Transgenic Mice; Tuberculosis; Vaccination; Vaccines; Virus Diseases; adaptive immunity; base; daughter cell; dietary; enzyme activity; fluidity; in vivo; innovation; liquid chromatography mass spectrometry; member; mouse model; novel; pathogenic virus; receptor; recruit; response; scaffold; selenium deficiency; selenoenzyme; selenoprotein; tool; vaccination protocol

Selenium (Se) is an essential micronutrient important for many aspects of human health, including optimal immune responses. The biological effects of Se are exerted mainly through its incorporation into selenoproteins as the amino acid, selenocysteine (Sec). Twenty-five selenoproteins have been identified in humans, all but one of which also exist as Sec-containing proteins in mice and rats. One selenoprotein that we have found to be important for optimal immune responses is the endoplasmic reticulum (ER) enzyme selenoprotein I (SELENOI). SELENOI expression is increased in stimulated T cells and is sensitive to levels of Se intake. The main goal of our research product is to fully understand the role that SELENOI plays in regulating T cell responses. Our central hypothesis is that SELENOI functions to synthesize phosphatidylethanolamine (PE) in the Kennedy synthesis pathway, and during activation of T cells there is increased demand for PE that requires higher levels of Se incorporated into SELENOI synthesized de novo. This in turn leads to higher levels of PE incorporated into cellular membranes. In conditions of low Se or genetic defects that reduce SELENOI expression and activity, membrane rigidity is compromised as well as other membrane properties that lead to impaired T cell signaling, proliferation, and differentiation. Our innovative studies will definitively determine the role of SELENOI in PE biosynthesis and how this affects T cell function and immune responses. We will accomplishment of the following specific aims: Specific Aim 1. To determine the role of SELENOI in PE synthesis in T cells and its requirement for establishing balanced membrane lipid composition and promoting robust TCR induced signals. Specific Aim 2. To elucidate mechanisms by which SELENOI promotes effective T cell proliferation and differentiation. Specific Aim 3. To determine the in vivo role of SELENOI in T cell responses to vaccines and a viral pathogen.

硒 (Se) 是一种必需的微量营养素，对人类健康的许多方面都很重要，包括最佳的免疫反应。 Se 的生物效应主要通过其以氨基酸硒代半胱氨酸 (Sec) 的形式掺入硒蛋白中来发挥。已在人类中鉴定出 25 种硒蛋白，其中除一种外，所有这些蛋白在小鼠和大鼠中也以含 Sec 的蛋白质形式存在。我们发现对于最佳免疫反应非常重要的一种硒蛋白是内质网 (ER) 酶硒蛋白 I (SELENOI)。 SELENOI 表达在受刺激的 T 细胞中增加，并且对硒摄入水平敏感。我们研究产品的主要目标是充分了解 SELENOI 在调节 T 细胞反应中的作用。我们的中心假设是，SELENOI 在肯尼迪合成途径中发挥合成磷脂酰乙醇胺 (PE) 的作用，并且在 T 细胞激活过程中，对 PE 的需求增加，需要将更高水平的 Se 掺入从头合成的 SELENOI 中。这反过来又导致更高水平的 PE 融入细胞膜。在低硒或遗传缺陷导致 SELENOI 表达和活性降低的情况下，膜刚性以及其他膜特性都会受到损害，从而导致 T 细胞信号传导、增殖和分化受损。我们的创新研究将明确确定 SELENOI 在 PE 生物合成中的作用以及它如何影响 T 细胞功能和免疫反应。我们将实现以下具体目标： 具体目标 1. 确定 SELENOI 在 T 细胞 PE 合成中的作用及其对建立平衡膜脂组成和促进稳健的 TCR 诱导信号的要求。具体目标 2. 阐明 SELENOI 促进有效 T 细胞增殖和分化的机制。具体目标 3. 确定 SELENOI 在 T 细胞对疫苗和病毒病原体反应中的体内作用。