Thromboregulation in Occlusive Vascular Diseases

闭塞性血管疾病中的血栓调节

• 批准号: 7657802
• 负责人: Aaron Jacob Marcus
• 金额: $ 73.06万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657802
• 关键词: ATP phosphohydrolase; Acute; Affect; Agonist; Alternative Splicing; Anabolism; Animal Model; Anus; Apyrase; Aspirin; Atherosclerosis; Autacoids; Biochemical; Biological; Blood; Blood Cells; Blood Platelets; Blood Vessels; Brain; Brain Diseases; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell membrane; Cells; Cerebrovascular Disorders; Cessation of life; Cholesterol; Clinical; Clinical Trials; Coagulation Process; Comprehension; Coronary; Coronary Arteriosclerosis; Coronary Occlusions; Data; Diagnosis; Disease; Drug Formulations; Eicosanoids; Endothelial Cells; Enzymes; Exhibits; Family suidae; Fibrinolytic Agents; Genes; Goals; Hemostatic function; Human; In Vitro; Inflammation; Ischemic Stroke; Knockout Mice; Lead; Length; Leukocytes; Liquid substance; Mediator of activation protein; Membrane Microdomains; Metabolic; Modality; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Nitric Oxide; Nucleotidases; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Platelet Activation; Prevention approach; Property; Prophylactic treatment; Prostaglandins I; Public Health; Publishing; RNA Splicing; Rattus; Recombinants; Recruitment Activity; Regulation; Research; Research Personnel; Safety; Signal Transduction; SolCD39; Stroke; Surface; System; Therapeutic; Thromboplastin; Thrombosis; Thrombus; Tissues; Variant; Vascular Diseases; atherothrombosis; base; cell type; ectoADPase; enzyme activity; fluidity; improved; in vivo; inhibitor/antagonist; monocyte; mortality; multidisciplinary; next generation; novel strategies; novel therapeutics; nucleotidase; prototype; public health relevance; response; tissue culture

DESCRIPTION (provided by applicant): Morbidity and mortality from stroke and coronary artery disease (CAD) are probably the most critical public health problems in the US. Both ischemic stroke and coronary occlusion are complications of atherosclerosis and inflammation which culminate in platelet activation, recruitment and vascular occlusion - a breach of the control of blood fluidity. Advances in therapeutic modalities for stroke and CAD have reached a plateau with an absence of novel approaches. The broad, long term objectives and specific aims of this proposal are to bring the ecto-enzyme CD39/NTPDase1 to clinical fruition via the in vitro and ex vivo studies described herein. Our recent studies of CD39 have demonstrated that it constitutes the main control system for blood fluidity (thromboregulation). CD39 has a unique mode of action whereby it inhibits platelet activation and recruitment, acting in the fluid phase. This occurs via metabolic deletion of prothrombotic ADP, the final common mediator in platelet-induced vascular occlusion. Thus the mechanism of action of CD39 is radically different from currently available therapeutic modalities for treatment of stroke and CAD. Our successful treatment of stroke with the soluble form of CD39 (solCD39) in 3 animal models, as previously published, suggests its safety and efficacy. Extensive preliminary molecular biology data indicate that expression of different CD39 alternative splice variants regulates CD39 expression, assembly into cholesterol-rich domains, and enzymatic and biological activity. This enhances our comprehension of the mechanisms of action of the enzyme, and its regulation. CD39 will be studied in cryptogenic and atherothrombotic stroke patients. Thus, we will evaluate the profile of CD39 variant expression in normals and patients with cryptogenic and atherothrombotic stroke. Platelet reactivity and markers of platelet activation will be evaluated in our cryptogenic and atherothrombotic patients and controls using a spectrum of platelet agonists and coagulation parameters, including circulating tissue factor, in the setting of their medication status. This also includes characterization of leukocyte-platelet aggregates (with emphasis on monocyte-platelet aggregates) and vascular cell-derived microparticles. We anticipate that our research will afford novel therapeutic opportunities for CD39 in prophylaxis and management of stroke and CAD. In this application we have developed a critical mass of patients and investigators in order to further our comprehension of the pathogenesis and treatment of platelet-driven cardiovascular diseases and to develop CD39 as the prototype of the next generation of antithrombotic agents. Thus, this revised submission is a broadly based multidisciplinary, molecularly and clinically focused application. PUBLIC HEALTH RELEVANCE: Vascular occlusion in the brain (stroke) is initiated by excessive blood platelet reactivity and recruitment, leading to extensive morbidity and mortality. This reactivity can be neutralized by the enzyme CD39. The relevance of this research is that it is provides a new and safe approach to the management of stroke for which there is no satisfactory treatment. We anticipate that the research proposed herein will lead to formulation of a clinical trial of a human soluble apyrase such as solCD39.

描述（由申请人提供）：中风和冠状动脉疾病（CAD）的发病率和死亡率可能是美国最关键的公共卫生问题。缺血性中风和冠状动脉闭塞都是动脉粥样硬化和炎症的并发症，最终在血小板激活，募集和血管闭塞中达到最终形式 - 违反了对血液流动的控制。中风和CAD的治疗方式的进步已经达到了一个平稳的水平，没有新的方法。该提案的广泛，长期目标和具体目的是通过本文所述的体外和离体研究将ecto-enzyme CD39/NTPDASE1带到临床上。我们对CD39的最新研究表明，它构成了血液流动性的主要控制系统（直血管调节）。 CD39具有独特的作用方式，可以抑制血小板的激活和募集，该作用在流体阶段。这是通过代谢缺失的促血栓形成ADP的，这是血小板诱导的血管闭塞的最终常见介体。因此，CD39的作用机理与当前可用的治疗方式用于治疗中风和CAD。如前所述，我们在3种动物模型中成功处理中风形式（SOLCD39）表明其安全性和有效性。广泛的初步分子生物学数据表明，不同CD39替代剪接变体的表达调节CD39的表达，组装成富含胆固醇的结构域以及酶促和生物学活性。这增强了我们对酶作用机理及其调节的理解。 CD39将在隐性和动脉粥样硬化中风患者中进行研究。因此，我们将评估CD39变异表达在正常质量和隐态性和动脉粥样硬化性中风的患者中的特征。血小板反应性和血小板激活的标志物将在我们的隐染性和动脉粥样硬化患者中评估，并使用一系列血小板激动剂和凝结参数（包括循环组织因子）在其药物状态的情况下进行评估。这还包括表征白细胞 - 血小板聚集体（重点是单核细胞 - 骨骼聚集体）和血管细胞衍生的微粒。我们预计我们的研究将为CD39提供预防和中风和CAD管理的新型治疗机会。在此应用中，我们开发了大量的患者和研究人员，以进一步理解血小板驱动的心血管疾病的发病机理和治疗，并将CD39作为下一代抗强化药物的原型开发。因此，该修订后的提交是一种基于广泛的多学科，分子和临床上的应用。公共卫生相关性：大脑中的血管阻塞（中风）是由血小板反应性过多和募集引发的，导致广泛的发病率和死亡率。这种反应性可以通过酶CD39中和。这项研究的相关性是，它为中风的管理提供了一种新的安全方法，没有令人满意的治疗方法。我们预计本文提出的研究将导致对诸如SOLCD39等人类可溶性蛋白酶的临床试验进行制定。