Investigating the dysfunction of the cerebral microvasculature in sickle cell disease

研究镰状细胞病中脑微血管的功能障碍

• 批准号: 9330437
• 负责人: Felicity Nicola Emma Gavins
• 金额: $ 36.25万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-17 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330437
• 关键词: Address; Adult; Affect; Age; Amino Acid Substitution; Animal Model; Antithrombins; Biological Markers; Blood Cells; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Brain; Cause of Death; Cell Adhesion; Cerebral Infarction; Cerebral Thrombosis; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Child; Chronic; Clinical; Coagulants; Coagulation Process; Comorbidity; Development; Diabetes Mellitus; Disease; Endothelial Cells; Erythrocytes; Functional disorder; Generations; Gold; Hereditary Disease; Histones; Hypertension; Impairment; Individual; Inflammation; Inflammatory; Ischemic Stroke; Leukocytes; Life; Link; Lung; Magnetic Resonance Imaging; Mediating; Modeling; Molecular; Multicellular Process; Mus; Neurologic Signs; Nuclear; Obesity; Organ; Pathway interactions; Patients; Phenotype; Platelet Activation; Platelet aggregation; Play; Production; Protein C; Reactive Oxygen Species; Risk Factors; Role; Sickle Cell; Sickle Cell Anemia; Stimulus; Stroke; Testing; Therapeutic; Thrombin; Thrombophilia; Thromboplastin; Thrombosis; Thrombus; Tissues; White Blood Cell Count procedure; arteriole; base; cerebral microvasculature; congenital heart disorder; extracellular; hemoglobin B; mortality; mouse model; mutant; neutrophil; response; venule

PROJECT SUMMARY/ABSTRACT Cerebrovascular disease is one of the leading causes of death in the USA, with more than 140,000 people dying each year from a stroke. While age remains the greatest risk factor for stroke, other conditions are also known to predispose individuals, including hypertension, obesity, diabetes and sickle cell disease (SCD). SCD in particular renders both adults and children vulnerable to ischemic stroke (e.g. 24% of SCD patients have a clinically apparent stroke by the age of 45 and 11% by the age of 20) and silent cerebral infarction ([SCI] which whilst quantifiable by MRI, produces no focal neurologic signs). It is therefore not surprising that SCD is frequently referred to as a “hypercoagulable state” characterized by a proinflammatory and prothrombogenic phenotype. Whilst the molecular origin of SCD is clear, the mechanisms that contribute to the prothrombogenic phenotype have not been fully elucidated. It is known that circulating neutrophils of SCD patients are activated and as such this has provided indirect evidence for their implication in thrombosis and vasoocclusive crises that accompany this condition. However, the actual role that neutrophils play and how they contribute directly to thrombus formation, especially in the brain, is currently unknown. We believe that by understanding the ways that neutrophils contribute not only to the systemic prothrombogenic phenotype of SCD, but more specifically to the actual local thrombosis, we will uncover the potential of targeting neutrophils as a therapeutic strategy for this debilitating and life threatening disease.

项目摘要/摘要 脑血管疾病是美国死亡的主要原因之一，有14万人 每年因中风而死。尽管年龄仍然是中风的最大风险因素，但其他情况也是 易感性个体已知，包括高血压，肥胖，糖尿病和镰状细胞病（SCD）。 SCD尤其使成人和儿童都容易受到缺血性中风（例如，24％的SCD患者 到20岁时，临床上的中风至45岁，而11％）和无声的脑梗塞 （[SCI]通过MRI进行量化，但没有产生局灶性神经系统迹象）。 因此，毫不奇怪的是，SCD经常被称为以A为特征的“超凝状态” 促炎和促血栓形成表型。虽然SCD的分子起源很明显，但 尚未完全阐明有助于促促促血栓表型的机制。众所周知 SCD患者的循环中性粒细胞被激活，因此为其提供了间接证据 适应这种情况的血栓形成和血管造成的危机的影响。但是，实际角色 中性粒细胞发挥的作用及其如何直接对血栓形成，尤其是在大脑中，是 目前未知。 我们相信，通过了解中性粒细胞不仅对系统性的贡献 SCD的促进蛋白表型，但更具体地针对实际的局部血栓形成，我们将发现 将嗜中性粒细胞作为这种衰弱和威胁生命的疾病的治疗策略的潜力。