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: 10159841
• 负责人: Peter R Hoffmann
• 金额: $ 44.97万
• 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/10159841
• 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; Protocols documentation; Publishing; Rattus; Receptor Signaling; Research; Role; Selenium; Selenocysteine; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; Structure; 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

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.

对于人类健康的许多方面，包括最佳免疫反应，硒（SE）是重要的微量营养素。 SE的生物学作用主要是通过将其掺入硒蛋白作为氨基酸硒代半胱氨酸（SEC）的生物作用。在人类中已经鉴定出25种硒蛋白，除一种外，所有甲蛋白蛋白也作为小鼠和大鼠中的含有SEC的蛋白质存在。我们发现对最佳免疫反应很重要的一种硒蛋白是内质网（ER）酶硒蛋白I（Selenoi）。在受刺激的T细胞中，硒代表的表达增加，并且对SE摄入水平敏感。我们的研究产品的主要目标是充分了解硒代中硒在调节T细胞反应中的作用。我们的中心假设是，硒可在肯尼迪合成途径中合成磷脂酰乙醇胺（PE），而在T细胞的激活期间，对PE的激活需求增加，需要更高水平的SE掺入Novo的Selenoi合成中。反过来，这导致较高水平的PE掺入细胞膜中。在降低硒表达和活性的低SE或遗传缺陷的条件下，膜刚度受到损害，以及其他导致T细胞信号传导，增殖和分化受损的膜特性。我们的创新研究将确定确定硒在PE生物合成中的作用，以及这如何影响T细胞功能和免疫反应。我们将实现以下特定目的：具体目的1。确定硒在T细胞中PE合成中的作用及其建立平衡的膜脂质组成并促进鲁棒TCR诱导的信号的要求。具体目的2。阐明硒代促进有效T细胞增殖和分化的机制。具体目的3。确定硒代反应在对疫苗和病毒病原体的T细胞反应中的体内作用。