Role of Hyperglycemia in Intracerebral Hemorrhage

高血糖在脑出血中的作用

• 批准号: 8842722
• 负责人: EDWARD P FEENER
• 金额: $ 36.67万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842722
• 关键词: Activated Partial Thromboplastin Time measurement; Admission activity; Adult; Adverse effects; Alteplase; Animal Model; Antibodies; Antisense Oligonucleotides; Apple; Area; Autologous; Binding; Biological; Blood; Blood Glucose; Blood Platelets; Blood Vessels; Bradykinin; Brain hemorrhage; Cerebral Edema; Cerebral Infarction; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Data; Coagulation Process; Collagen; Complication; Diabetes Mellitus; Edema; Enzymes; Event; Experimental Models; Glucose; Grant; Hematoma; Hemorrhage; Hemostatic function; Hyperglycemia; Hypertension; Impairment; Injection of therapeutic agent; Injury; Insulin; Interruption; Intervention; Intravenous; Ischemia; Ischemic Stroke; Macroglobulins; Maps; Mediating; Modeling; Molecular; Names; Neurologic; Outcome; Pathway interactions; Patients; Peptides; Physiological; Plasma Kallikrein; Platelet Activation; Platelet Aggregation Inhibition; Platelet aggregation; Pre-Clinical Model; Prevention; Proteins; Rattus; Receptor Activation; Reporting; Risk; Risk Factors; Rodent Model; Role; Series; Spontaneous Rupture; Streptozocin; Stroke; System; Therapeutic; Thromboembolism; Time; Treatment outcome; Vascular Permeabilities; acute stroke; blood glucose regulation; cerebral artery; cerebrovascular; disability; mortality; mouse model; novel; preclinical study; response

DESCRIPTION (provided by applicant): Diabetes is associated with a 2 to 6-fold increased risk of stroke, which is a leading cause of mortality and adult disability. Stroke is often associated with intracerebral hemorrhage (ICH), which occurs as the primary event in hemorrhagic stroke and can also occur spontaneously following an initial ischemia event, especially during thrombolytic intervention. Both diabetes and hyperglycemia are associated with worse clinical outcomes following ICH, including increased early and long-term mortality, occurrence of symptomatic ICH in stroke patients treated with intravenous tissue plasminogen activator (tPA), and increased hematoma volume and expansion, which are significant and independent determinants of poor clinical outcomes. Although a large amount of clinical data has associated diabetes and hyperglycemia with poor clinical outcomes, and nearly 50% of all acute stroke patients have hyperglycemia upon admission, the effects of glucose and its related mechanisms on ICH are poorly understood. Moreover, information on the clinical benefit of glucose lowering in ICH is limited and controversial, and the potential therapeutic window for glucose lowering is unknown. Recently we have reported that hyperglycemia increases hematoma formation in rodent models of ICH and that this response is mediated by plasma kallikrein. The mechanisms for this response involved a glucose sensitive plasma kallikrein-mediated inhibition of platelet activation, which interfered with collagen-induced GPVI receptor activation. These studies have revealed a novel function of plasma kallikrein in the inhibition of platelet aggregation, which is an early event in establishing hemostasis following cerebral vascular injury. In preliminary studies, we have demonstrated that hyperglycemia also increases hematoma area in both tPA and in hypertension-induced models of spontaneous ICH, and we have begun to map the functional domain on plasma kallikrein that is responsible for its inhibitory effects of platelet activation. These exciting findings have suggested that plasma kallikrein actions are glucose sensitive and that this enzyme has previously unrecognized effects in the coagulation system. This grant will examine the potential therapeutic opportunities using glucose control and new strategies to inhibit PK to reduce ICH in a series of preclinical studies to develop and characterize findings using multiple experimental models and molecular interventions. The mechanisms that mediate the effects of plasma kallikrein will be characterized by identifying the structural domain on this protein that mediates this anti-platelet effect, which we have shown does not require plasma kallikrein's catalytic activity. Since a major complication associated with ICH is its effects on edema, we will examine the effects of insulin and plasma kallikrein inhibition on the prevention and reversal of ICH-induced edema. This grant will examine the hypothesis that the direct effects of plasma kallikrein on hemostasis and peri-hematomal edema contribute to the poor ICH outcomes in diabetes and hyperglycemia.

描述（由申请人提供）：糖尿病与中风风险增加2至6倍相关，中风是导致死亡和成人残疾的主要原因。脑卒中常伴有脑出血（ICH），这是出血性卒中的主要事件，也可在初始缺血事件后自发发生，特别是在溶栓干预期间。糖尿病和高血糖都与脑出血后较差的临床结果相关，包括早期和长期死亡率增加，静脉注射组织型纤溶酶原激活剂（tPA）治疗的脑卒中患者出现症状性脑出血，血肿体积和扩张增加，这些都是不良临床结果的重要和独立决定因素。虽然大量的临床数据表明糖尿病和高血糖与不良的临床预后有关，而且近50%的急性脑卒中患者入院时患有高血糖，但葡萄糖对脑出血的影响及其相关机制尚不清楚。此外，关于脑出血降糖的临床益处的信息是有限的和有争议的，潜在的降糖治疗窗口是未知的。最近，我们报道了高血糖增加脑出血啮齿动物模型的血肿形成，这种反应是由血浆钾激肽介导的。这种反应的机制涉及葡萄糖敏感血浆钾化钾素介导的血小板激活抑制，这干扰了胶原诱导的GPVI受体激活。这些研究揭示了血浆钾化管在抑制血小板聚集中的新功能，这是脑血管损伤后建立止血的早期事件。在初步研究中，我们已经证明，在tPA和高血压诱导的自发性脑出血模型中，高血糖也会增加血肿面积，并且我们已经开始绘制血浆钾激肽的功能区域，该功能区域负责抑制血小板活化。这些令人兴奋的发现表明血浆钾激肽肽的作用是葡萄糖敏感的，并且这种酶在凝血系统中具有以前未被认识到的作用。该基金将在一系列临床前研究中研究使用葡萄糖控制和抑制PK以减少脑出血的新策略的潜在治疗机会，以开发和表征使用多种实验模型和分子干预的结果。介导血浆钾激肽作用的机制将通过鉴定介导这种抗血小板的这种蛋白质的结构域来表征