Analysis of Tgsl, a novel regulator of macrophage survival

巨噬细胞存活的新型调节剂 Tgsl 的分析

• 批准号: 8719001
• 负责人: Victor L Boyartchuk
• 金额: $ 19.88万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719001
• 关键词: 3' Untranslated Regions; Affect; Antigens; Apoptotic; Arterial Fatty Streak; Atherosclerosis; C57BL/6 Mouse; Cell Survival; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Chromosomes, Human, Pair 4; Data; Disease; Disease Progression; Down-Regulation; Early Diagnosis; Elements; Environment; Equilibrium; Excision; Exposure to; Genes; Genetic; Genetic Polymorphism; Goals; Health; Heart Diseases; Immune; Immune response; Immune system; Inbred BALB C Mice; Infection; Inflammation; Inflammatory; Interferons; Invaded; Knowledge; Length; Ligands; Listeria monocytogenes; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; Myeloid Cells; Necrosis; Nuclear Hormone Receptors; Nuclear Receptors; Organism; Outcome; Pathogenesis; Pathway interactions; Physiological Processes; Play; Polyadenylation; Post-Transcriptional Regulation; Process; Production; Protein Overexpression; Proteins; RXR; Reactive Oxygen Species; Recruitment Activity; Regulation; Regulatory Element; Repression; Resistance; Role; Rupture; Series; Signal Transduction; Site; Staging; Stroke; Structure; T-Lymphocyte; Translational Regulation; Untranslated Regions; base; cytokine; design; improved; insight; killings; lipid metabolism; macrophage; novel; oxidized lipid; pathogen; protein expression; research study; response; reverse cholesterol transport; trait; uptake

DESCRIPTION (provided by applicant): Macrophages perform a wide range of functions, from defense against pathogens to removal of toxic products of metabolism. As such macrophages are involved in pathogenesis of a large number of infectious, inflammatory and metabolic diseases. The LXR nuclear hormone receptor pathway plays a key role in regulation of macrophage viability. LXR ligands are oxidized lipids and LXR signaling controls the expression of proteins involved in lipid metabolism. In addition LXR controls the expression of molecules involved in inflammation, including CD5L, a macrophage survival factor. We identified TGS1 as a novel regulator of CD5L that is tightly repressed by 3' UTR cis regulatory elements. Significantly, our data show that repression of TGS1 production is relieved in response to LPS, resulting in down-regulation of CD5L. LPS appears to exert its effect by inducing utilization of an upstream alternative Tgs1 polyadenylation site. Our discoveries provide a strong support for TGS1 as a molecule that connects inflammatory and metabolic signaling. We propose to carry out a set of experiments that will 1. Determine the mechanism of post-transcriptional control of Tgs12. Identify regulators of TGS1 post-transcriptional control machinery. By pursuing the proposed aims we will identify trans effectors that act on TGS1 3'UTR cis control elements and characterize TGS1 targets. Moreover we will confirm the role of inducible alternative polyadenylation in regulation of the LXR pathway that controls viability of macrophages. Results of our study will reveal novel details of cross-regulation of metabolic and inflammatory pathways and will therefore have a broad impact on our understanding of pathogenesis of a wide range of diseases

描述(申请人提供)：巨噬细胞执行广泛的功能，从防御病原体到清除有毒的新陈代谢产物。因此，巨噬细胞参与了大量感染性、炎症性和代谢性疾病的发病过程。LXR核激素受体通路在巨噬细胞活性调节中起关键作用。LXR配体是氧化的脂类，LXR信号控制着与脂代谢有关的蛋白质的表达。此外，LXR还控制与炎症有关的分子的表达，包括巨噬细胞生存因子CD5L。我们发现TGS1是CD5L的一个新的调节因子，受到3‘UTR顺式调节元件的紧密抑制。值得注意的是，我们的数据表明，内毒素对TGS1产生的抑制作用得到缓解，导致CD5L下调。脂多糖似乎通过诱导利用一种 上游选择性Tgs1多聚腺苷酸化位点。我们的发现为TGS1作为连接炎症和代谢信号的分子提供了强有力的支持。我们建议开展一系列实验，以1.确定TGS12转录后调控的机制。确定TGS1转录后调控机制的调节者。通过追求拟议的目标，我们将确定作用于TGS1 3‘非编码区顺式调控元件的反式效应器，并表征TGS1靶标。此外，我们将确认可诱导的选择性多聚腺苷在调节LXR通路中的作用，该通路控制巨噬细胞的活性。我们的研究结果将揭示代谢和炎症途径的交叉调节的新细节，因此将对我们理解一系列疾病的发病机制产生广泛的影响