The Role of LRP in the Activation of Invariant Natural Killer T Cells

LRP 在恒定自然杀伤 T 细胞激活中的作用

• 批准号: 8529882
• 负责人: Roman Covarrubias
• 金额: $ 2.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529882
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apolipoprotein E; Autoimmunity; Binding; Cells; Chronic; Data; Dendritic Cells; Disease; Disease Progression; Drug or chemical Tissue Distribution; Environment; Event; Future; Galactosylceramides; Genetic; Glycolipids; Goals; Homeostasis; Host Defense; Hour; Human; Hyperlipidemia; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Infection; Inflammatory; Investigation; Knockout Mice; Knowledge; LDL-Receptor Related Proteins; Laboratories; Lead; Lipids; Lipoproteins; MHC Class I Genes; Malignant Neoplasms; Measures; Mediating; Metabolism; Mus; Myelogenous; Neoplasm Metastasis; Pathway interactions; Phenotype; Physiologic pulse; Physiological; Physiological Processes; Play; Process; Protein Deficiency; Regulation; Research; Research Design; Role; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Work; anergy; combat; cytokine; granulocyte; immune function; killer T cell; macrophage; melanoma; mouse model; novel; protein expression; public health relevance; receptor; response; tumorigenesis; uptake

DESCRIPTION (provided by applicant): The long term goal of this project is to understand a novel physiological mechanism that mediates activation of the immune system. Specifically, the ability of a special subset of immune cells termed invariant natural killer T cells (iNKT). Once activated these iNKT cells have the ability to secrete large amounts of cytokines that can activate the immune system within hours: as opposed to conventional T cells which can take 4-6 days. It is thought that due to the rapid response of iNKT cells they serve to alter disease progression. Activation of iNKT cells require the presentation of antigenic lipids in the context o molecule CD1d. This CD1d-dependent presentation appears to be altered in conditions of hyperlipidemia where increased levels of circulating lipids are present. Our laboratory has produced preliminary data showing that a receptor previously known to be involved in lipoprotein metabolism, the LDL receptor related protein (LRP), can play a role in iNKT cell activation. Therefore the hypothesis of this proposal is that LRP plays a role in glycolipid antige uptake and subsequent NKT cell activation. We propose two related but independent specific aims to test this hypothesis. In the first aim of this proposal we will examine the ability of LRP n APCs to make antigens available to iNKT cells. This will be done by using a mouse model with a genetic deletion of LRP in APCs. On the second aim, we will measure the ability of iNKT cells from these mice to function properly and whether deletion of LRP can lead to long term deficiencies in iNKT cell activation. In this aim we will also test the significant physiological relevance of impaired iNKT cell activation by testing the ability mice deficient in LRP to halt tumorigenesis in a mouse model of melanoma. Ultimately, the studies designed on this proposal will enhance our knowledge of normal physiological processes that can affect immune function.

描述（由申请人提供）：该项目的长期目标是了解一种介导免疫系统激活的新型生理机制。具体而言，特殊的免疫细胞的特殊子集称为不变的天然杀伤细胞（INKT）。一旦激活，这些Inkt细胞就可以分泌大量的细胞因子，这些细胞因子可以在数小时内激活免疫系统：与可能需要4-6天的常规T细胞相反。人们认为，由于inkt细胞的快速反应，它们用于改变疾病进展。 Inkt细胞的激活需要在上下文中呈现抗原脂质O分子CD1D。在存在循环脂质水平升高的高脂血症的条件下，这种依赖CD1D依赖性的表现似乎正在改变。我们的实验室产生了初步数据，表明先前已知参与脂蛋白代谢，LDL受体相关蛋白（LRP）的受体可以在Inkt细胞激活中发挥作用。因此，该提议的假设是LRP在糖脂抗体摄取和随后的NKT细胞激活中起作用。我们提出了两个相关但独立的目的，以检验这一假设。在该提案的第一个目的中，我们将研究LRP N APC使iNKT细胞可用的抗原的能力。这将通过使用APC中LRP的遗传缺失的小鼠模型来完成。在第二个目标上，我们将测量这些小鼠的Inkt细胞正常运行的能力，以及LRP的缺失是否会导致inkt细胞激活中的长期缺陷。在此目标中，我们还将通过测试缺乏LRP的能力小鼠在黑色素瘤小鼠模型中停止肿瘤发生的能力小鼠来测试受损细胞激活的显着生理相关性。最终，根据该提案设计的研究将增强我们对可能影响免疫功能的正常生理过程的了解。