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）仍然是世界世界世界世界世界世界世界内的领先原因，它通常与 血脂异常，氧化应激和米氏功能障碍。 在AS的发展中起着至关重要的作用。 导致脂质内和泡沫细胞的积累 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受体 表面一个主要问题是oxldl导致CD36表达 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。 定义了新的调节器，是多PI提案的核心目标的核心目标。 预后研究表明，PIM1是一种保守的丝氨酸/苏氨酸激酶可调节CD36的转录 此外，巨噬细胞中PIM1基因的遗传消融导致PPARγ途径进行了修复以及 我们因此涉及脂肪事故代谢和米奇氧化磷酸化的靶标 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。 在巨噬细胞中有助于促动脉粥样硬化的表型和AS。 巨噬细胞中PIM1激酶坐在PPARγ激活/CD36表达的分子机制 和模块化脂肪酸代谢的mitchonial功能。 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激酶调节脂肪事故代谢的机制PPARγ/CD36途径； 确定PIM1激酶通过DRP-1和 定义对线粒体脂肪活化，氧化磷酸化和ROS产生的影响。 将检验以下假设：在体内灭活PIM1激酶会抑制AS的发展。 遗传PIM1烧蚀模型和PIM Inhivitor AZD1208的微小注入，我们旨在测试您 假设PIM1活性对于饮食引起的不可或缺 PIM1的药理学非自由度抑制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； 在动脉粥样硬化条件下调节骨髓 - 单局局部分化谱系 阐明PIM1激酶协调脂肪酸代谢和 线粒体功能以控制巨噬细胞在大生殖条件下的激活，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。