eNOS polymorphisms and cerebral vasospasm after SAH

描述（由申请人提供）：eNOS多态性和SAH后的脑血管痉挛。 脑血管痉挛是蛛网膜下腔出血（SAH）的常见并发症，也是动脉瘤破裂后死亡和致残的主要原因。脑血管痉挛的病因可能是多因素的，但最终导致血管内皮细胞对脑血流量（CBF）的调节改变。我们的数据也支持内皮型一氧化氮（eNOS）多态性在增加脑血管痉挛易感性中的作用。我们建议通过测量定量CBF并与SAH后脑血管痉挛患者的结局相关来研究eNOS多态性对血流调节的影响。在我们的300例SAH患者（2003年建立）的纵向队列中，我们收集了血液、血清和CSF样本，并仔细描述了急性住院期间的临床和影像学表现。此外，我们还收集了SAH后两年内的功能和认知结果。遗传易感性与中间表型、定量CBF和相关临床结果的进一步相关性将构成未来R01资助申请的基础，以研究脑血管痉挛和缺血中CBF的调节。为了更好地了解eNOS多态性在脑血管痉挛中的作用，我们将在我们的回顾性队列中确定eNOS多态性、脑血管痉挛和不良神经学结局之间的相关性。我们还将进行一项前瞻性的初步研究，以确定最高风险基因型与CBF生理改变的相关性。本研究的目的是提供与临床结果改变NOS活性相关的遗传变异的证据。此外，我们将开发一组中间表型，这将使我们能够更好地了解赋予eNOS多态性遗传易感性的生物学机制。本研究的长期目标是了解脑血管痉挛的病理生理学，为高危患者开发更好的预测模型，并确定新的干预靶点，以改善临床结局。

DESCRIPTION (provided by applicant): eNOS polymorphisms and cerebral vasospasm after SAH. Cerebral vasospasm is a common complication of aneurysmal subarachnoid hemorrhage (SAH) and remains a major cause of death and disability after aneurysm rupture. The etiology of cerebral vasospasm is likely multi-factorial but eventually leads to altered cerebral blood flow (CBF) regulation by the vascular endothelium. Our data also supports the role of endothelial nitric oxide (eNOS) polymorphisms in increasing susceptibility for cerebral vasospasm. We propose to study the effect of polymorphisms in eNOS on blood flow regulation by measuring quantitative CBF and correlating with outcomes in patients with cerebral vasospasm after SAH. In our longitudinal cohort of 300 SAH patients (established in 2003), we have collected blood, serum, and CSF samples, and we have carefully characterized clinical and radiographic findings during the acute hospitalization. In addition, we have collected functional and cognitive outcomes up to two years after SAH. Further correlation of genetic susceptibility with an intermediate phenotype, quantitative CBF, and relevant clinical outcomes will form the basis of a future R01 grant application to investigate regulation of CBF in cerebral vasospasm and ischemia. In order to better understand the role of polymorphisms in eNOS in cerebral vasospasm, we will determine the association between eNOS polymorphisms, cerebral vasospasm and adverse neurological outcomes in our retrospective cohort. We will also perform a prospective pilot study to determine the association of the highest risk genotypes with physiologic alterations in CBF. The goal of this research is to provide evidence for genetic variation associated with altered NOS activity with clinical outcome. Further, we will develop a set of intermediate phenotypes that will enable us to better understand the biologic mechanisms that confer genetic susceptibility from eNOS polymorphisms. The long-term goals of this research are to understand the pathophysiology of cerebral vasospasm, to develop better predictive models for patients at risk, and to identify novel targets for intervention that will improve clinical outcomes.