Targeting Pyruvate Kinase M2: A novel strategy to combat thrombo-inflammation

靶向丙酮酸激酶 M2：对抗血栓炎症的新策略

• 批准号: 10600854
• 负责人: Anil Kumar Chauhan
• 金额: $ 75.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600854
• 关键词: Acute; Animal Model; Anti-Inflammatory Agents; Antiplatelet Drugs; Aspirin; Biological Models; Blood Platelets; Cardiovascular Diseases; Clinical; Coronary Arteriosclerosis; Data; Disease; Economic Burden; Economics; Energy Metabolism; Enzymes; Exhibits; Genetic; Glucose; Glycoproteins; Goals; Guidelines; Health; Hemorrhage; Hyperlipidemia; Industry; Inflammation; Inflammatory; Ischemic Stroke; Leukocytes; Macrophage; Malignant Neoplasms; Mus; Myelogenous; Normal Cell; Oxidative Phosphorylation; Oxygen; Patients; Pharmaceutical Preparations; Phenotype; Productivity; Pyruvate Kinase; Reagent; Research; Resolution; Rest; Risk; Role; Scientist; Stroke; Testing; Thrombosis; United States; Update; abciximab; acute coronary syndrome; aerobic glycolysis; bench to bedside; clinical efficacy; combat; dimer; experience; high reward; high risk; improved; improved outcome; inhibitor; innovation; intravital microscopy; monocyte; mouse model; mutant; new therapeutic target; novel; novel strategies; pharmacologic; pre-clinical; prevent; programs; response; stroke model; stroke outcome; stroke therapy; success; therapeutic target; thromboinflammation; tool

Project summary Cardiovascular disease (CVD) and stroke claim more lives than all forms of cancer combined and result in an immense health and economic burden (>$316 billion annually in the United States). Current strategies to prevent acute coronary syndromes and ischemic stroke in at risk patients rely on anti-platelet drugs (e.g. aspirin and P2Y12 inhibitors), which do not translate into clinical efficacy in 1/3rd of patients. More potent anti- platelet agents such as Glycoprotein IIbIIIa inhibitors (e.g. abciximab) are associated with bleeding complications and are not suitable for long-term use. Since CVD and stroke are characterized by thrombosis and inflammation, an ideal drug would be one that inhibits thrombo-inflammatory responses without major bleeding and activates inflammation resolution programs leading to polarization of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory) phenotype. To accomplish this, we are exploring an innovative strategy to inhibit thrombo-inflammation by manipulating aerobic glycolysis in activated platelets and leukocytes. Our approach will be to target the key regulatory enzyme of aerobic glycolysis, pyruvate kinase M2 (PKM2). This approach takes advantage of the recent discovery that, like most normal cells, resting platelets and leukocytes rely primarily on oxidative phosphorylation to generate ATP, whereas activated platelets and leukocytes exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen). Notably, recent evidence indicates that PKM2 is highly expressed in the monocytes and macrophages from patients with coronary artery disease, and a driver of M1 macrophage polarization. Utilizing novel mutant platelet-specific PKM2 deficient and myeloid-specific PKM2 deficient strains, we have generated preliminary data that suggests a role for PKM2 in modulating thrombo-inflammation. The goals of this research program are to further understand how PKM2 regulates platelet and leukocyte function and to determine if targeting dimeric PKM2 will inhibit thrombo-inflammation in a murine model of hyperlipidemia. To promote the success of this innovative and high reward program, we will utilize complementary genetic and pharmacological approaches and state-of-the art intravital microscopy, and follow updated Stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines. We have all the tools, including reagents and state-of-the art intravital microscopy and animal models, to accomplish our goals. I have the prerequisite experience as evidenced by my track record, which has shown high productivity and an upward trajectory in the field of thrombo-inflammation. I have assembled a group of basic scientists and clinicians whose expertise will help guide the proposed research from bench to clinic. This project has significant clinical implications since a clear understanding of energy metabolism and its functional consequences on platelet and leukocyte function could identify novel therapeutic targets common to both thrombosis and inflammation, which may improve outcomes in patients at high risk for thrombo-inflammatory disorders including acute ischemic stroke.

项目摘要 心血管疾病（CVD）和中风的寿命比所有形式的癌症都多，并导致 巨大的健康和经济负担（美国每年> 3160亿美元）。当前的策略 预防危险患者的急性冠状动脉综合征和缺血性中风依赖于抗血清药物（例如 阿司匹林和P2Y12抑制剂），在1/3患者中不会转化为临床疗效。更有效的反 - 血小板剂，例如糖蛋白IIBIIIA抑制剂（例如abciximab）与出血有关 并发症，不适合长期使用。由于CVD和中风的特征是血栓形成 和炎症，一种理想的药物将是抑制血栓炎性反应而没有重大的药物 出血并激活炎症解决方案，导致M1的极化 （促炎）到M2（抗炎）表型。为此，我们正在探索创新 通过在活化的血小板中操纵有氧糖酵解来抑制血栓炎的策略 白细胞。我们的方法是针对有氧糖酵解，丙酮酸激酶M2的关键调节酶 （PKM2）。这种方法利用了最近的发现，即与大多数普通细胞一样静止血小板 白细胞主要依赖氧化磷酸化来产生ATP，而活化的血小板和 白细胞表现出高水平的有氧糖酵解（在存在的情况下葡萄糖转化为乳酸 氧）。值得注意的是，最近的证据表明PKM2在单核细胞中高度表达，并且 来自冠状动脉疾病患者的巨噬细胞和M1巨噬细胞极化的驱动因素。利用 新型突变体血小板特异性PKM2缺乏和髓样特异性PKM2缺乏菌株，我们已经产生了 初步数据表明PKM2在调节血栓炎症中的作用。这项研究的目标 程序将进一步了解PKM2如何调节血小板和白细胞功能，并确定是否是否 靶向二聚体PKM2将抑制高脂血症的鼠模型中的血栓炎。促进 这个创新和高奖励计划的成功，我们将利用互补的遗传和 药理方法和最先进的插入式显微镜，并遵循更新的中风疗法 学术行业圆桌会议（楼梯）临床前指南。我们有所有工具，包括试剂和 最先进的插入式显微镜和动物模型，以实现我们的目标。我有先决条件 我的往绩记录证明了经验，这表现出很高的生产率和向上的轨迹 血栓炎的领域。我聚集了一群基础科学家和临床医生，他们的专业知识 将有助于指导从板凳到诊所的拟议研究。该项目具有重大的临床意义 由于对能量代谢及其对血小板和白细胞的功能后果有清晰的了解 功能可以识别血栓形成和炎症共有的新型治疗靶标，这可能 改善血栓炎性疾病（包括急性缺血性中风）高风险患者的预后。