Lipid-dependent regulation of human Th17 cell function

人类 Th17 细胞功能的脂质依赖性调节

• 批准号: 9176733
• 负责人: Jun R. Huh
• 金额: $ 44.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176733
• 关键词: Adverse effects; Arthritis; Autoimmune Diseases; Autoimmune Process; Biogenesis; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chemicals; Colitis; Cytoplasm; Data; Development; Disease; Disease model; Effector Cell; Family; Fatty Acids; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genetic screening method; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Kinetics; Lead; Ligands; Light; Link; Lipids; Liver diseases; Memory; Metabolic; Metabolism; Modeling; Molecular; Multiple Sclerosis; Mus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Organelles; Orphan; PPAR gamma; Pathology; Pathway interactions; Physiological; Play; Polyunsaturated Fatty Acids; Production; Proteins; Psoriasis; Regulation; Regulatory T-Lymphocyte; Retinoids; Role; Specificity; Sterols; T cell differentiation; T-Lymphocyte; Testing; Triglycerides; abstracting; chemical genetics; cytokine; gain of function; knock-down; lipid metabolism; macromolecule; novel; novel therapeutics; programs; receptor; response; small hairpin RNA; small molecule; treatment strategy

Abstract Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (RORγt), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify RORγt target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, RORγt activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by RORγt target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes – specifically, HILPDA and BNIP3 – are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.

抽象的 Th17细胞是白细胞介素17的CD4+ T效应细胞的子集，是中心的 从炎症性肠中实施了许多人类炎症和自身免疫性疾病 多发性硬化症的疾病。类维生素类孤儿受体伽马T（RORγT），一种核骑马 接收器，程序Th17细胞开发和功能。以调节的最终目标 疾病环境中的炎性T细胞，我们对化学和遗传筛查进行了 识别驱动人类Th17细胞功能的RORγT靶基因。有趣的是，我们的结果 在新的途径中实现了一组基因，该基因将连接脂质代谢，RORγT活性 和Th17细胞功能。因此，我们将检验以下假设，即Th17细胞功能受到控制 大部分，通过rorγT靶基因，通过脂质液滴（LDS）（与 脂质代谢）。我们将采用以下方法：首先，我们将确定是否相关 基因 - 特别是HILPDA和BNIP3 - 是必要的，足够的，具体的调节剂 人Th17细胞功能。其次，我们将阐明LDS的分子机制 调节Th17细胞分化。第三，使用小鼠的自身免疫性疾病模型，我们将 确定LDS在炎症和自身免疫性病理中的身体意义。 我们的结果可能会阐明控制TH17细胞的新型脂质调节机制 炎症性疾病的反应。