Effect of zinc on tPA induced thrombolysis

锌对 tPA 诱导溶栓的影响

• 批准号: 10047089
• 负责人: YANG V LI
• 金额: $ 45.3万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047089
• 关键词: Acute; Address; Affect; Age; Aging; Alpha Granule; Alteplase; American; Atrial Fibrillation; Attenuated; Blood Circulation; Blood Platelets; Blood coagulation; Blood flow; Brain; Brain Death; Brain Injuries; Brain Ischemia; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cerebral hemisphere hemorrhage; Chelating Agents; Cholesterol; Clinical Trials; Coagulation Process; Combined Modality Therapy; Complex; Detection; Diabetes Mellitus; Dose; Embolism; Excision; FDA approved; Failure; Fibrin; Fibrin fragment D; Fibrinolytic Agents; Glucose; Goals; Heart Diseases; Hemorrhage; Hour; Hypertension; In Vitro; Interruption; Intervention; Ions; Ischemic Stroke; Laboratories; Letters; Literature; Measures; Medical; Metals; Methods; Middle Cerebral Artery Occlusion; Modality; Modeling; Myocardial Infarction; Nerve Degeneration; Nervous System Trauma; Neurons; Obesity; Oxygen; Pathologic; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Platelet aggregation; Play; Population; Procedures; Protocols documentation; Publications; Publishing; Reperfusion Therapy; Reporting; Research; Research Activity; Research Priority; Risk; Risk Factors; Role; Route; Safety; Seizures; Serum; Site; Smoking; Societies; Source; Spectrophotometry; Streptokinase; Stroke; Students; Testing; Therapeutic; Therapeutic Index; Thrombosis; Thrombotic Stroke; Thrombus; Time; Toxic effect; Training; Translational Research; United States; United States National Institutes of Health; Whole Blood; Work; Yang; Zinc; aging population; base; chelation; cytotoxicity; deprivation; disability; effective therapy; improved; improved functioning; in vivo; neuron loss; neurovascular unit; novel; novel therapeutics; preclinical study; prevent; professor; side effect; stroke outcome; stroke patient; stroke therapy; therapeutic effectiveness; therapy outcome; thromboembolic stroke; thrombolysis

Stroke is the second leading cause of death worldwide, and the fifth leading cause of death in the US. With the aging of the population, the number of stroke patients is likely to grow. Despite enormous research efforts including many clinical trials, effective therapy has remained elusive. A large number of previous preclinical studies was performed on non-embolic stroke, which could be one of the factors for translational failure. Tissue plasminogen activator (tPA) remains the only FDA-approved treatment for acute ischemic stroke. Unfortunately, only 2-5% of stroke patients in the US receive this therapy because of the narrow time window and severe side effects for using tPA. The most deadly and damaging side effect of tPA is the risk of intracranial bleeding or hemorrhage. For that reason, the dose of tPA and its overall administration are under tight control, while the effect of thrombolysis may be compromised. Studies have been focused on improving efficacy of tPA for higher rate of reperfusion, and for enhancement of safety and less adverse bleeding episode. In this proposal, we will investigate how metal ion zinc (Zn2+) affect thrombolysis in vitro and in vivo. We have proposed a method to improve tPA-induced thrombolysis. The overall hypothesis behind the proposed research is that study is that the presence of Zn2+ alters tPA-induced thrombolysis. This hypothesis is based on the following key observations based on the available literature, and our published and preliminary studies: 1st. In the bloodstream there is the most Zn2+-enriched site, α-granule of platelets, where the zinc concentration reaches 500µM (almost 30 fold higher zinc level in platelets than in the serum). 2nd. Zn2+ play critical roles in blood coagulation and platelets aggregation. 3rd. During the clot formation, a large amount of Zn2+ are released from platelets leading to the surge in Zn2+ concentrations in the local microenvironment and subsequent platelet aggregation. Therefore, thrombi become a source of Zn2+ as Zn2+ is “trapped” in the thrombi. 4th. Results from our published study showed that Zn2+ attenuated streptokinase-induced thrombolysis. In the preliminary studies, we observed the similar interaction between Zn2+ and tPA. The specific Aim 1 will determine the effect of Zn2+ on tPA-induced thrombolysis in vitro. Specific Aim 2 will investigate the promoting effect of Zn2+ chelation on tPA-induced thrombolysis in embolic MCAO in vivo. The major finding in the preliminary study is that Zn2+ has an inhibitory effect on thrombolysis when it is co-applied with tPA. We hypothesize that Zn2+ chelation can facilitate the tPA-induced thrombolysis in the clot model of ischemic stroke. The application of smaller amount tPA, in combination with a zinc chelator, can achieve the same or better therapeutic outcome in the treatment of stroke. Therefore, this proposal is a basic translation research addressing priorities of NIH stroke research, and addressing complex issues such as timing, therapeutic window, cytotoxicity and reperfusion of a potential combination therapy.

中风是全球死亡的第二大原因，也是美国第五大死亡原因。与 人口老龄化，中风患者的数量可能会增加。尽管进行了巨大的研究工作 包括许多临床试验，有效的治疗仍然难以捉摸。大量以前的临床前 对非胎儿中风进行了研究，这可能是翻译失败的因素之一。组织 纤溶酶原激活物（TPA）仍然是急性缺血性中风的唯一FDA批准的治疗方法。 不幸的是，由于时间狭窄，美国只有2-5％的中风患者接受了这种疗法 和使用TPA的严重副作用。 TPA最致命，最具破坏性的副作用是 颅内出血或出血。因此，TPA的剂量及其整体管理已受到 严格的控制，而溶栓的作用可能会受到损害。研究的重点是改善 TPA的功效对于更高的再灌注率以及增强安全性和不良出血的功效 插曲。在此提案中，我们将研究金属离子锌（Zn2+）如何在体外和体内影响溶栓。 我们提出了一种改善TPA诱导的溶栓的方法。背后的总体假设 拟议的研究是，研究是Zn2+的存在改变了TPA诱导的溶栓。这个假设是 基于以下基于可用文献的关键观察以及我们发表的初步观察 研究：第一。在血液中，有最多的Zn2+富集位点，α颗粒的血小板，其中锌 浓度达到500µm（血小板的锌水平几乎比血清高30倍）。第二。 Zn2+播放 在血液凝血和血小板聚集中的关键作用。第三在凝块形成期间，大量 Zn2+是从血小板中释放的，导致局部微环境中的Zn2+浓度激增 随后的血小板聚集。因此，血栓成为Zn2+的来源，因为Zn2+被“捕获” 血栓。第四。我们发表的研究的结果表明，Zn2+减弱链球菌酶诱导的 溶栓。在初步研究中，我们观察到Zn2+和TPA之间的相似相互作用。这 具体目标1将确定Zn2+在体外对TPA诱导的溶栓分解的影响。具体目标2将 研究Zn2+螯合对体内栓塞MCAO中TPA诱导的溶栓的促进作用。这 初步研究中的主要发现是，Zn2+对溶栓具有抑制作用。 与TPA。我们假设Zn2+螯合可以促进TPA诱导的溶栓模型 缺血性中风。较小量TPA的应用与锌螯合剂结合使用，可以实现 中风治疗时相同或更好的治疗结果。因此，该建议是基本的翻译 研究涉及NIH中风研究的优先事项，并解决了计时等复杂问题， 潜在组合疗法的治疗窗口，细胞毒性和再灌注。