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.

项目概要 动脉粥样硬化是心血管疾病的主要原因，约占死亡人数的 30% (859,125) 在美国，每年估计直接医疗费用为 2187 亿美元。晚期患者 动脉粥样硬化阶段会出现危及生命的并发症，如心肌梗塞、缺血性心脏病等。 中风、动脉瘤和多器官衰竭。目前有许多治疗选择，例如抗血小板和抗血小板药物 凝血疗法虽然可以成功缓解或预防动脉粥样硬化的血栓形成事件，但 出血和出血并发症的风险。因此，显然有必要进一步了解 止血和血栓形成的分子基础，以便开发更安全、更有效的疗法。 在这方面，最近令人感兴趣的一组治疗药物是酪氨酸激酶抑制剂（TKI）。酪氨酸激酶 针对布鲁顿酪氨酸激酶 (BTK) 的抑制剂，包括依鲁替尼，传统上被广泛使用 成功治疗血液恶性肿瘤，例如慢性淋巴细胞白血病（CLL），以及 炎症，例如类风湿性关节炎。由于 BTK 的核心作用也存在于血小板中 最近，BTK 抑制剂作为一种潜在的抗血小板药物进行了研究，并证明了其效果 对抗动脉粥样硬化斑块引发的血栓形成；然而，血小板 BTK 的机制 被激活，其功能效果在很大程度上仍然不明确。 为此，我们的建议旨在表征血小板中 BTK 的调节（目标 1）和功能效应 BTK（目标 2）在动脉粥样硬化中的作用，以减少血栓并发症，同时尽量减少对止血的影响。到 研究血小板BTK在动脉粥样硬化中的作用，1）我们将首次汇集生理学 和磷酸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。 我们项目的潜在转化相关性将是鉴定安全且可成药的分子 血小板激活途径中的靶点和机制。我们的研究最终可能会提供理由 经典 BTK 抑制剂作为二级抗血小板和抗血栓药物的开发和使用 可以安全地使患有动脉粥样硬化及其并发症的患者受益。