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

基本信息

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
项目类别：
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

项目摘要

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，每年晚期患者的直接医疗费用估计为 2187 亿美元。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。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，但因此，显然需要进一步了解出血和出血并发症的风险。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）。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系统恶性肿瘤，例如慢性淋巴细胞白血病（CLL），以及炎症性疾病，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，并证明了其效果然而，血小板 BTK 对抗动脉粥样硬化斑块引发的血栓形成的机制；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。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，描述调节信号激活血小板中 BTK 的级联；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我们的研究可能最终为血小板激活途径中的靶点和机制提供理论依据。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。