Thymidine Phosphorylase: a Novel Target of Antiplatelet Therapy

胸苷磷酸化酶：抗血小板治疗的新靶点

• 批准号: 10448031
• 负责人: Wei Li
• 金额: $ 44.4万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448031
• 关键词: 2019-nCoV; ACE2; Accident and Emergency department; Acute Respiratory Distress Syndrome; Address; Agonist; Antiplatelet Drugs; Atherosclerosis; Attenuated; Biology; Blood Coagulation Disorders; Blood Platelets; C-reactive protein; COVID-19; COVID-19 mortality; COVID-19 patient; COVID-19 treatment; Chemicals; Clinical; Collagen; Complex; Complication; Cytoplasm; Cytoplasmic Protein; Cytosol; Data; Development; Diabetes Mellitus; Dimerization; Disease; Disseminated Intravascular Coagulation; Dose; Drug usage; Event; FDA approved; Fibrin fragment D; Fibrinolytic Agents; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; General Hospitals; Goals; Hemorrhage; Hemostatic function; Human; Individual; Inflammation; Inflammatory; Ischemic Stroke; Lactate Dehydrogenase; Lead; Lentivirus; Life; Lung; Malignant Neoplasms; Massachusetts; Mediating; Molecular; Multiple Organ Failure; Mus; Myocardial Infarction; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylase a; Plasma; Platelet Activation; Platelet Glycoproteins; Platelet aggregation; Play; Predictive Factor; Process; Proteins; Risk; Role; SARS-CoV-2 infection; SARS-CoV-2 positive; SARS-CoV-2 spike protein; SH3 Domains; Severity of illness; Signal Pathway; Signal Transduction; Stroke; Systemic disease; Testing; Thrombin; Thrombocytopenia; Thrombosis; Thrombus; Thymidine Phosphorylase; Transgenic Organisms; Viral; Virus; antagonist; autocrine; beta-arrestin; cardiovascular risk factor; cohort; cremaster muscle; cytokine release syndrome; desensitization; inhibitor; insight; mortality; mouse model; novel; pandemic disease; paracrine; platelet function; prevent; pulmonary symptom; recruit; respiratory; severe COVID-19; side effect; src-Family Kinases; thrombotic

Project Summary/Abstract Platelet activation and aggregation is a major component of thrombosis, an underlying cause of myocardial infarction, ischemic stroke, and severe COVID-19, a new viral respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Various antiplatelet drugs are used clinically to prevent thrombosis. These drugs block platelet activation and aggregation systemically and, thus, have side effects (e.g., thrombocytopenia and hemorrhage). Therefore, new molecular mechanism-mediated antiplatelet and antithrombotic therapies are urgently needed. We recently discovered that thymidine phosphorylase (TYMP), a highly expressed protein in platelet cytosol, facilitates multiple agonist-induced platelet activation. TYMP haploinsufficiency or inhibition with its inhibitors significantly attenuates arterial thrombosis without disturbing systemic hemostasis. Most importantly, TYMP is increased in COVID-19 patients in an acuity-dependent manner. Increased plasma TYMP in COVID-19 patients occurs earlier than the increase in C-reactive protein, a predictive factor for inflammation and future risk of cardiovascular events. Increased TYMP is also positively associated with plasma D-dimer and lactate dehydrogenase levels and the presence of pulmonary symptoms. These findings indicate that TYMP may play a critical role in the development of severe COVID-19, and modulation of TYMP activity could potentially be a systemically safe therapy against COVID-19. To this end, it is necessary to elucidate the detailed mechanistic pathways of TYMP in platelet activation and thrombosis. We have clarified the role of TYMP in the platelet signaling pathway mediated by platelet glycoprotein VI (GPVI). However, we still do not know how TYMP deficiency or inhibition attenuates G-protein coupled receptor (GPCR)-mediated platelet activation and what TYMP’s role is in the hyperthrombotic milieu of severe COVID- 19. We will address these questions in the proposed specific aims. In Aim1, we will clarify the function of TYMP in GPCR-mediated platelet activation using specific GPCR agonists and antagonists and test the hypothesis that a combination of low-dose TYMP inhibitor and GPCR antagonist represents a new, safe dual antiplatelet therapy. In Aim 2, we will determine whether the SARS-CoV-2 spike protein enhances TYMP expression and subsequent microthrombi formation in the COVID-19 milieu. We will also investigate if TYMP deficiency or inhibition attenuates SARS-CoV-2 spike protein-associated microthrombosis and reduces mortality in mice. Our ongoing study suggest that pharmacological inhibition of TYMP with tipiracil, a selective TYMP inhibitor and an FDA-approved medication, is a promising anti-thrombotic therapy without bleeding disorders. Successful completion of this R15 renewal will pave the way for repurposing tipiracil as an antiplatelet medication for patients with high thrombotic risks, especially COVID-19 patients.

项目摘要/摘要 血小板活化和聚集是血栓形成的主要成分，血栓是心肌梗死的根本原因。 脑梗塞、缺血性卒中和严重新冠肺炎，一种新的由严重急性呼吸道疾病引起的疾病 呼吸综合征冠状病毒-2(SARS-CoV-2)。临床上使用各种抗血小板药物来预防 血栓形成。这些药物系统性地阻断了血小板的激活和聚集，因此有副作用。 (例如，血小板减少和出血)。因此，新的分子机制介导的抗血小板和 迫切需要抗血栓治疗。我们最近发现胸苷磷酸化酶(TYMP)，一种 在血小板胞浆中高表达的蛋白，促进多种激动剂诱导的血小板激活。TYMP 单倍体功能不全或用其抑制剂抑制显著减轻动脉血栓形成而不干扰 全身止血。最重要的是，新冠肺炎患者的屈光度增加与视力呈正相关 举止。新冠肺炎患者血浆酪氨酸蛋白升高先于C反应蛋白升高， 炎症和未来心血管事件风险的预测因素。增加的TYMP也是积极的 与血浆D-二聚体和乳酸脱氢酶水平及肺部症状的存在有关。 提示TYMP在重症新冠肺炎的发生、发展中可能起重要作用。 调节酪氨酸蛋白的活性可能是一种对新冠肺炎具有系统安全性的治疗方法。为此，它 有必要阐明TYMP在血小板活化和血栓形成中的详细机制。我们 阐明了TYMP在血小板膜糖蛋白VI(GPVI)介导的血小板信号通路中的作用。 然而，我们仍然不知道TYMP缺乏或抑制如何减弱G蛋白偶联受体 (GPCR)介导的血小板激活以及TYMP在严重COVID-血栓形成环境中的作用- 19.我们会在拟议的具体目标中处理这些问题。在Aim1中，我们将澄清TYMP的功能 使用特异性gpcr激动剂和拮抗剂在gpr介导的血小板活化中的作用，并检验假设 小剂量TYMP抑制剂和GPCR拮抗剂联合应用代表了一种新的、安全的双重抗血小板药物 心理治疗。在目标2中，我们将确定SARS-CoV-2刺突蛋白是否增强TYMP的表达和 随后在新冠肺炎环境中形成微血栓。我们还将调查TYMP缺乏症或 抑制可减轻SARS-CoV-2刺突蛋白相关的微血栓形成，并降低小鼠的死亡率。 我们正在进行的研究表明，TYMP的药理抑制作用与TYMP的选择性抑制剂替吡啶有关 这是一种FDA批准的药物，是一种很有前途的抗血栓疗法，没有出血障碍。 R15更新的成功完成将为将替吡拉西重新用作抗血小板药物铺平道路 血栓形成风险高的患者，尤其是新冠肺炎患者的用药。