Role of Platelet Bruton's Tyrosine Kinase (BTK) in Atherosclerosis

血小板布鲁顿酪氨酸激酶 (BTK) 在动脉粥样硬化中的作用

• 批准号: 10549282
• 负责人: Tony Zheng
• 金额: $ 5.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549282
• 关键词: Accounting; Address; Affect; Agammaglobulinaemia tyrosine kinase; Aneurysm; Anticoagulant therapy; Antiplatelet Drugs; Arterial Fatty Streak; Atherosclerosis; B-Lymphocytes; Binding; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Collagen; Data; Development; Drug Targeting; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Family; Fibrinolytic Agents; Functional disorder; Future; G-Protein-Coupled Receptors; Glycoproteins; Health Care Costs; Hematologic Neoplasms; Hematopoietic; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Hyperactivity; ITAM; Inflammation; Inflammatory; Interest Group; Ischemic Stroke; Leukocytes; Life; Maps; Mediating; Membrane Proteins; Methods; Microfluidics; Modeling; Molecular; Molecular Target; Multiple Organ Failure; Myocardial Infarction; Pathologic; Pathway interactions; Patients; Phosphotransferases; Physiological; Platelet Activation; Play; Process; Protein Tyrosine Kinase; Regulation; Reporting; Research; Rheumatoid Arthritis; Risk; Role; Rupture; Signal Pathway; Signal Transduction; Site; Stenosis; Surface; System; TLR2 gene; Techniques; Therapeutic; Therapeutic Intervention; Thrombosis; Thrombus; Time; Tyrosine Kinase Inhibitor; United States; atherosclerotic plaque rupture; combinatorial; cytokine; effective therapy; endothelial dysfunction; extracellular; interest; member; novel; phosphoproteomics; platelet function; prevent; receptor; recruit; repaired; response; shear stress; success; thrombotic; thrombotic complications; translational potential; translational study

Project Summary Atherosclerosis is the leading cause of cardiovascular disease, accounting for nearly 30% (859,125) of deaths in the United States, with an estimated direct healthcare cost of $218.7 billion every year. Patients with late stage atherosclerosis suffer from life-threatening complications, such as myocardial infarctions, ischemic strokes, aneurysms, and multi-organ failure. Many current treatment options, such as anti-platelet and anti- coagulant therapies, although successfully alleviating or preventing thrombotic events of atherosclerosis, carry a risk for bleeding and hemorrhagic complications. Thus, there is a clear need to further understand the molecular basis of hemostasis and thrombosis in order develop safer and more effective therapies. In this regard, one recent therapeutic group of interest is tyrosine kinase inhibitors (TKIs). Tyrosine kinase inhibitors targeting Bruton’s tyrosine kinase (BTK), including ibrutinib, have traditionally been used with great success in treating hematological malignancies, such as chronic lymphocytic leukemia (CLL), and inflammatory conditions, such as rheumatoid arthritis. Due to the central role of BTK also seen in platelet activation, BTK inhibitors have recently been studied as a potential anti-platelet agent, demonstrating effects against atherosclerotic plaque-triggered thrombus formation; however, the mechanisms by which platelet BTK is activated and its functional effects remain largely ill-defined. To this end, our proposal aims to characterize in platelets the regulation of BTK (Aim 1) and functional effects of BTK (Aim 2) in atherosclerosis, to reduce thrombotic complications while minimally affecting hemostasis. To investigate the role of platelet BTK in atherosclerosis, 1) we will bring together for the first time physiological and phosphoproteomics methods to perform a combinatorial analysis delineating the regulatory signaling cascades that activate BTK in platelets; and 2) we will define the effects of BTK activation on platelet functional responses and investigate the interplay between platelets, endothelial cells, and leukocytes classically seen at the microenvironment of atherosclerotic plaque rupture. The potential translational relevance of our project will be the identification of safe and druggable molecular target and mechanisms within the platelet activation pathway. Our research may ultimately provide rationale for the development and use of classic BTK inhibitors as secondary anti-platelet and anti-thrombotic agents that could safely benefit patients who suffer from atherosclerosis and its complications.

项目摘要 动脉粥样硬化是心血管疾病的主要原因，占死亡的近30％（859,125） 在美国，每年的直接医疗保健估计为2187亿美元。迟到的患者 阶段动脉粥样硬化遭受威胁生命的并发症，例如心肌梗死，缺血性 中风，动脉瘤和多器官衰竭。许多当前的治疗选择，例如抗血小板和抗 - 凝结剂疗法虽然成功地减轻或预防动脉粥样硬化的血小板事件，但携带 出血和出血并发症的风险。那很明显需要进一步了解 止血和血栓形成的分子基础，以开发更安全，更有效的疗法。 在这方面，最近的一个治疗群是酪氨酸激酶抑制剂（TKIS）。 传统上使用了针对布鲁顿酪氨酸激酶（BTK）的抑制剂（BTK），传统上与 成功治疗血液系统恶性肿瘤，例如慢性淋巴细胞性白血病（CLL）和 炎性疾病，例如类风湿关节炎。由于BTK的核心作用在血小板中也有 激活，BTK抑制剂最近已被研究为潜在的抗血小板剂，证明了影响 针对动脉粥样硬化斑块触发的血栓形成；但是，血小板BTK的机制 被激活，其功能效应在很大程度上定义不明。 为此，我们的建议旨在表征血小板的BTK调节（AIM 1）和功能效应 在动脉粥样硬化中的BTK（AIM 2），以减少血栓形成并发症，同时最小化止血。到 研究血小板BTK在动脉粥样硬化中的作用，1）我们将首次汇集 和磷蛋白质组学方法进行组合分析描述调节信号传导 激活血小板中BTK的级联反应； 2）我们将定义BTK激活对血小板功能的影响 反应并研究血小板，内皮细胞和白细胞之间经典的相互作用 动脉粥样硬化斑块破裂的微环境。 我们项目的潜在翻译相关性将是确定安全且可吸毒的分子 血小板激活途径内的目标和机制。我们的研究最终可能为 经典BTK抑制剂的开发和使用，作为次级抗血小板和抗栓性药物 可以安全地使患有动脉粥样硬化及其并发症的患者受益。