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.

项目概要/摘要 脑血管疾病是美国的主要原因之一，有超过 140,000 人死于脑血管疾病 每年都会死于中风，虽然年龄仍然是中风的最大危险因素，但其他情况也是如此。 已知会导致个体易感，包括高血压、肥胖、糖尿病和镰状细胞病 (SCD)。 SCD 尤其使成人和儿童容易发生缺血性中风（例如 24% 的 SCD 患者 45 岁时有临床明显的中风，20 岁时有 11%）和无症状脑梗塞 （[SCI] 虽然可以通过 MRI 量化，但不会产生局灶性神经系统体征）。 因此，SCD 经常被称为“高凝状态”，其特征是 虽然 SCD 的分子起源很清楚，但 已知导致血栓形成表型的机制尚未完全阐明。 SCD 患者的循环中性粒细胞被激活，因此这为他们的治疗提供了间接证据。 然而，伴随这种情况的血栓形成和血管闭塞危机的影响。 中性粒细胞的作用以及它们如何直接促进血栓形成，特别是在大脑中， 目前未知。 我们相信，通过了解中性粒细胞不仅对系统性 SCD 的促血栓表型，但更具体地说，对于实际的局部血栓形成，我们将揭示 以中性粒细胞为靶标作为治疗这种使人衰弱和危及生命的疾病的策略的潜力。