Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages

Pim1 激酶协调 PPAR gamma 通路和线粒体功能，介导巨噬细胞中的促动脉粥样硬化反应

• 批准号: 10372226
• 负责人: WEIGUO CUI
• 金额: $ 41.69万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372226
• 关键词: Ablation; Adopted; Atherosclerosis; Attenuated; Binding; Biochemical; Bone Marrow; CD36 gene; Cause of Death; Cells; Collaborations; Coupled; Data; Development; Diet; Disease; Dynamin; Dyslipidemias; Fatty Acids; Feedback; Foam Cells; Genetic; Genetic Transcription; Goals; Immune; Immunologics; Infusion procedures; Interleukin-6; Intracellular Accumulation of Lipids; Knowledge; Ligands; Link; Lipids; Macrophage Activation; Mediating; Metabolic Pathway; Mitochondria; Modeling; Molecular; Morphology; Mus; Nuclear Hormone Receptors; Oxidative Phosphorylation; Oxidative Stress; PIM1 gene; PPAR gamma; Pathway interactions; Pharmacology; Phenotype; Phosphotransferases; Play; Process; Production; Protein-Serine-Threonine Kinases; Proteins; Publishing; Resistance; Role; Signal Transduction; Site; Stat3 protein; Surface; Testing; Therapeutic Intervention; Up-Regulation; base; fatty acid metabolism; fatty acid oxidation; immune activation; in vivo; inhibitor; lipid metabolism; macrophage; metabolic abnormality assessment; metabolic profile; mitochondrial dysfunction; monocyte; new therapeutic target; novel; novel therapeutic intervention; oxidized low density lipoprotein; response; scavenger receptor; transcription factor; treatment strategy; uptake

Atherosclerosis (AS) remains the leading cause of death world-wide and it is often associated with dyslipidemia, oxidative stress and mitochondrial dysfunction. Macrophage is a type of innate immune cell that plays a critical role in the development of AS. Unrestricted uptake of oxidized LDL (oxLDL) by macrophages leads to accumulation of lipid intracellularly and foam cell formation, which is a hallmark of early stages of AS. OxLDL uptake is mainly mediated by CD36, a scavenger receptor highly expressed on the macrophage surface. One major problem is that oxLDL leads to up-regulation of CD36 expression through a transcription factor PPARγ, resulting in a positive feedback mechanism to further enhance CD36-mediated oxLDL uptake. Defining the novel regulator of this process is the central goal of this multi-PI proposal. Recent published and preliminary studies showed that Pim1, a conserved serine/threonine kinase regulates CD36 transcription. In addition, genetic ablation of pim1 gene in macrophages resulted in a reduction in PPARγ pathway as well as the downstream targets involved in fatty acid metabolism and mitochondrial oxidative phosphorylation. We thus hypothesized that Pim1 kinase coordinates PPARγ activation/CD36 expression and mitochondrial functions to regulate fatty acid metabolism and immune activation in macrophages. Continuous stimulation of Pim1 kinase in macrophages contributes to pro-atherogenic phenotypes and AS. Specific aim 1 will determine the molecular mechanism by which Pim1 kinase in macrophages coordinates PPARγ activation/CD36 expression and mitochondrial function to modulate fatty acid metabolism. We will use a combination of genetically modified macrophages, biochemical, immunological and ex vivo cell metabolic studies to determine the mechanisms by which Pim1 kinase regulates fatty acid metabolism through the PPARγ/CD36 pathway; and to determine the mechanisms by which Pim1 kinase regulates mitochondria morphology through Drp-1 and define the impact on mitochondria fatty acid oxidation, oxidative phosphorylation and ROS production. Aim 2 will test the hypothesis that inactivating Pim1 kinase in vivo suppresses the development of AS. Using the genetic pim1 ablation model and minipump infusion of the Pim inhibitor AZD1208, we aim to test the hypothesis that Pim1 activity is indispensible for diet-induced AS in mice; and to test the hypothesis that pharmacologic inhibition of Pim1 suppresses PPARγ/CD36 pathway and reprograms macrophage mitochondria toward ROS production under atherogenic conditions; and test the hypothesis that Pim1 regulates bone marrow-monocyte-macrophage differentiation lineage under atherogenic conditions. By elucidating the molecular mechanisms by which Pim1 kinase coordinates fatty acid metabolism and mitochondrial functions to control macrophage activation under atherogenic conditions, we expect to gain crucial knowledge on novel lipid metabolism regulators and provide new treatment strategies against AS.

动脉粥样硬化（AS）仍然是全球死亡的主要原因，并且通常与 血脂异常，氧化应激和线粒体功能障碍。巨噬细胞是一种先天免疫细胞 在AS的发展中起关键作用。巨噬细胞对氧化的LDL（OXLDL）的不受限制摄取 导致细胞内脂质的积累和泡沫细胞的形成，这是AS早期阶段的标志。 OXLDL吸收主要由CD36介导，CD36是一种高度表达巨噬细胞的清道夫接收器 表面。一个主要问题是OXLDL通过转录导致CD36表达上调 因子PPARγ，产生了积极的反馈机制，以进一步增强CD36介导的OXLDL摄取。 定义此过程的新型调节器是该多PI提案的核心目标。最近出版和 初步研究表明，PIM1是一种配置的丝氨酸/苏氨酸激酶可调节CD36转录。在 此外，巨噬细胞中PIM1基因的遗传消融导致PPARγ途径的降低以及 涉及脂肪酸代谢和线粒体氧化磷酸化的下游靶标。我们这样 假设PIM1激酶会坐在PPARγ激活/CD36表达和线粒体功能 调节巨噬细胞中的脂肪酸代谢和免疫激活。连续刺激PIM1激酶 在巨噬细胞中有助于促动脉粥样硬化的表型和AS。具体目标1将确定 巨噬细胞中PIM1激酶坐在PPARγ激活/CD36表达的分子机制 线粒体功能调节脂肪酸代谢。我们将使用一般的组合 改良的巨噬细胞，生化，免疫学和离体细胞代谢研究，以确定 PIM1激酶通过PPARγ/CD36途径调节脂肪酸代谢的机制；然后 确定PIM1激酶通过DRP-1和 定义对线粒体脂肪酸氧化，氧化磷酸化和ROS产生的影响。目标2 将检验以下假设：在体内灭活PIM1激酶会抑制AS的发展。使用 遗传PIM1消融模型和PIM抑制剂AZD1208的小型注入，我们旨在测试 假设PIM1活性对于小鼠的饮食引起的不可或缺。并检验假设 PIM1的药理抑制抑制PPARγ/CD36途径并重新编程巨噬细胞 线粒体在动脉粥样硬化条件下朝着ROS产生；并检验PIM1的假设 调节在动脉粥样硬化条件下的骨髓 - 单核细胞巨噬细胞分化谱系。经过 阐明PIM1激酶协调脂肪酸代谢和 线粒体功能以控制动脉粥样硬化条件下的巨噬细胞激活，我们期望获得 关于新型脂质代谢调节剂的关键知识，并提供了针对AS的新治疗策略。