Role of Hyperglycemia in Intracerebral Hemorrhage

高血糖在脑出血中的作用

基本信息

批准号：
8373511
负责人：
EDWARD P FEENER
金额：
$ 37.94万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8373511
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Diabetes and high blood glucose levels are associated with increased bleeding during hemorrhagic stroke, resulting in worse clinical outcomes. Recent studies have revealed that an enzyme named plasma kallikrein contributes an impairment to control cerebral bleeding in animal models with diabetes. This grant will perform mechanistic studies to characterize this newly identified function of plasma kallikrein and preclinical studies to examine potential therapeutic opportunities in reducing cerebral bleeding by controlling blood glucose and inhibiting plasma kallikrein.

描述（由申请人提供）：糖尿病与中风风险增加2至6倍，这是死亡率和成人残疾的主要原因。中风通常与脑出血（ICH）相关，后者是出血性中风中的主要事件，并且在初始缺血事件后也可以自发发生，尤其是在溶栓干预期间。糖尿病和高血糖均与ICH之后的临床结局较差有关，包括早期和长期死亡率增加，症状性ICH的发生在用静脉内组织纤溶酶原激活剂（TPA）治疗的中风患者中，以及血肿的体积和膨胀增加，这是较差的和独立的临床确定性。尽管大量的临床数据与临床结局相关，糖尿病和高血糖症与临床结局差，并且所有急性中风患者中有近50％在入院后患有高血糖，但葡萄糖及其相关机制对ICH的影响知之甚少。此外，有关ICH中葡萄糖降低的临床益处的信息有限且有争议，并且降低葡萄糖的潜在治疗窗口尚不清楚。最近，我们报道了高血糖会增加ICH啮齿动物模型中的血肿形成，并且该反应是由血浆kallikrein介导的。该反应的机制涉及葡萄糖敏感的等离子体kallikrein介导的血小板激活抑制，该抑制会干扰胶原蛋白诱导的GPVI受体激活。这些研究揭示了血浆kallikrein在抑制血小板聚集中的新功能，这是在脑血管损伤后建立止血的早期事件。在初步研究中，我们已经证明高血糖还会增加TPA和高血压诱导的自发ICH模型中的血肿区域，并且我们开始在血浆Kallikrein上的功能结构域绘制造成其血小板激活的抑制作用的血浆Kallikrein上的功能结构域。这些令人兴奋的发现表明，血浆kallikrein的作用是葡萄糖敏感的，并且该酶以前在凝结系统中没有认可的作用。该赠款将使用葡萄糖控制和新策略来检查潜在的治疗机会，以抑制PK以减少一系列临床前研究，以使用多种实验模型和分子干预措施来开发和表征发现。介导等离子kallikrein作用的机制将以鉴定该蛋白质的结构结构域的特征效果，我们已经显示的不需要等离子体卡利克林的催化活性。由于与ICH相关的主要并发症是其对水肿的影响，因此我们将检查胰岛素和血浆kallikrein抑制对ICH诱导的水肿的预防和逆转的影响。该赠款将研究以下假设：血浆kallikrein对止血和血肿性水肿的直接影响有助于糖尿病和高血糖的不良ICH结果。公共卫生相关性：糖尿病和高血糖水平与出血性中风期间出血的增加有关，从而导致临床结果较差。最近的研究表明，一种名为血浆kallikrein的酶有助于控制患有糖尿病动物模型的脑出血。该赠款将进行机械研究，以表征血浆Kallikrein和临床前研究的新鉴定的功能通过控制血糖和抑制血浆kallikrein来检查潜在的治疗机会来减少脑出血。