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

项目摘要 动脉粥样硬化是心血管疾病的主要原因，占死亡人数的近30%（859，125） 在美国，估计每年的直接医疗费用为2187亿美元。晚期患者 阶段性动脉粥样硬化会出现危及生命的并发症，例如心肌梗塞、缺血性 中风动脉瘤和多器官衰竭目前的许多治疗选择，如抗血小板和抗 凝血剂疗法虽然成功地减轻或预防了动脉粥样硬化的血栓形成事件， 出血和出血性并发症的风险。因此，显然需要进一步了解 止血和血栓形成的分子基础，以开发更安全，更有效的治疗方法。 在这方面，一个最近的治疗组的利益是酪氨酸激酶抑制剂（TKI）。酪氨酸激酶 靶向布鲁顿氏酪氨酸激酶（BTK）的抑制剂，包括伊曲替尼，传统上已被广泛使用， 成功治疗血液恶性肿瘤，如慢性淋巴细胞白血病（CLL）， 炎性病症，如类风湿性关节炎。由于BTK的中心作用也见于血小板 活化，BTK抑制剂最近已被研究作为一种潜在的抗血小板剂，证明效果 抗动脉粥样硬化斑块触发的血栓形成;然而，血小板BTK 被激活，其功能作用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（目的1）和功能效应 BTK（目的2）在动脉粥样硬化中的应用，以减少血栓形成并发症，同时最大限度地影响止血。到 研究血小板BTK在动脉粥样硬化中的作用，1）我们将首次汇集生理性 和磷酸化蛋白质组学方法来进行描述调节信号传导的组合分析 2）我们将确定BTK活化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。 我们项目的潜在翻译相关性将是鉴定安全和可药用的分子 血小板活化途径中的靶点和机制。我们的研究最终可能会为以下方面提供理论依据： 开发和使用经典BTK抑制剂作为二级抗血小板和抗血栓形成剂， 可以安全地使患有动脉粥样硬化及其并发症的患者受益。

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.