Investigating the dysfunction of the cerebral microvasculature in sickle cell disease

项目总结/摘要 脑血管疾病是美国死亡的主要原因之一，有超过14万人 每年死于中风虽然年龄仍然是中风的最大危险因素，但其他条件也是 已知易患病个体，包括高血压、肥胖症、糖尿病和镰状细胞病（SCD）。 SCD尤其使成人和儿童都容易发生缺血性卒中（例如，24%的SCD患者 到45岁时有临床上明显的中风，到20岁时有11%）和无症状性脑梗死 （[SCI]虽然可通过MRI定量，但不产生局灶性神经学体征）。 因此，SCD经常被称为“高凝状态”并不奇怪，其特征在于： 促炎和促血栓形成表型。虽然SCD的分子起源是清楚的， 导致促血栓形成表型的机制尚未完全阐明。已知的是 SCD患者的循环中性粒细胞被激活，因此这为SCD患者的免疫功能提供了间接证据。 与血栓形成和血管闭塞性危象有关。然而，实际作用 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的促血栓形成表型，但更具体地说，对实际的局部血栓形成，我们将揭示 靶向中性粒细胞作为这种使人衰弱和危及生命的疾病的治疗策略的潜力。

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.