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

基本信息

批准号：
10209655
负责人：
WEIGUO CUI
金额：
$ 42.34万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
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/10209655
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/antagonist 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

项目摘要

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) 仍然是全世界死亡的主要原因，它通常与血脂异常、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。巨噬细胞对氧化低密度脂蛋白 (oxLDL) 的不受限制的摄取在 AS 的发生中发挥着关键作用。导致细胞内脂质积累和泡沫细胞形成，这是 AS 早期的标志。 OxLDL 摄取主要由巨噬细胞上高表达的清道夫受体 CD36 介导一个主要问题是 oxLDL 通过转录导致 CD36 表达上调。 PPARγ 因子，产生正反馈机制，进一步增强 CD36 介导的 oxLDL 摄取。定义该过程的新型监管者是最近发布的多 PI 提案的中心目标。初步研究表明，Pim1（一种保守的丝氨酸/苏氨酸激酶）调节 CD36 转录。此外，巨噬细胞中 pim1 基因的基因消除导致 PPARγ 通路减少以及下游靶标涉及脂肪酸代谢和线粒体氧化磷酸化。保留了 Pim1 激酶协调 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，持续刺激 Pim1 激酶。巨噬细胞中的有助于促动脉粥样硬化表型和 AS。具体目标 1 将确定。巨噬细胞中 Pim1 激酶协调 PPARγ 激活/CD36 表达的分子机制我们将结合基因和线粒体功能来调节脂肪酸代谢。修饰巨噬细胞、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；确定 Pim1 激酶通过 Drp-1 调节线粒体形态的机制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。将验证体内 Pim1 激酶失活可抑制 AS 发展的假设。遗传 pim1 消融模型和 Pim 抑制剂 AZD1208 的微型泵输注，我们的目的是测试假设 Pim1 活性对于小鼠饮食诱导的 AS 是必不可少的；并检验以下假设： Pim1 的药理学抑制可抑制 PPARγ/CD36 通路并重新编程巨噬细胞线粒体在致动脉粥样硬化条件下产生 ROS；并检验 Pim1 的假设；在致动脉粥样硬化条件下调节骨髓-单核细胞-巨噬细胞分化谱系。阐明 Pim1 激酶协调脂肪酸代谢的分子机制线粒体功能在动脉粥样硬化条件下控制巨噬细胞活化，我们期望获得新型脂质代谢调节剂的重要知识，并提供针对 AS 的新治疗策略。