Biochemical Mechanisms of Cerebral Vasospasm

脑血管痉挛的生化机制

• 批准号: 6678027
• 负责人: JOSEPH Floyd CLARK
• 金额: $ 36.1万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678027
• 关键词: animal tissue; bilirubin; cerebral hemorrhage; cerebral ischemia /hypoxia; cerebrospinal fluid; clinical research; disease /disorder model; enzyme activity; human tissue; laboratory rat; molecular pathology; myosins; oxidation; phosphatase inhibitor; phosphoprotein phosphatase; subarachnoid space; vascular smooth muscle; vasoconstriction; vasoconstrictors; vasospasm

DESCRIPTION (provided by applicant): Vasospasm is a frequent cause of delayed ischemic stroke in subarachnoid hemorrhage (SAH) patients. In this project we will evaluate the molecule(s) that are responsible for causing SAH-induced cerebral vasospasm. The cause of the vasospasm is largely unknown but it has been suggested to be due to a vasoactive molecule in the hemorrhagic CSF. We have found that bilirubin oxidation products (BOXes) are found in the CSF of SAH patients and propose that the BOXes are phosphatase inhibitors that can cause cerebral vasospasm. There have been three structurally related molecules identified. These molecules produce prolonged contractile effects on the vessels in vivo and in vitro that are strikingly similar to the prolonged vasospasm seen from the CSF of SAH patients with vasospasm. We suggest that smooth muscle protein phosphatase inhibition causes prolonged vasospasm. Moreover it is the BOXes that are the phosphatase inhibitors that produce prolonged vasospasm in patients following subarachnoid hemorrhage. In Aims #1 and #2 using cranial window technique, we will examine the time course of cerebral vasospasm in rats caused by the BOXes, and will assess the potency of the individual BOXes. The degree of vascular constriction will be studied over 14 days and the brain examined for evidence of damage. In Aim #3 we will show that BOXes inhibit phosphatases and that this leads to vasospasm using porcine basilar artery in vitro. The long-term goal for this project is to define the molecular causes of vasospasm (such as bilirubin oxidation products, phosphatase inhibition) in order to develop effective diagnostic, therapeutic and preventative approaches for this cerebral vascular disease.

描述（由申请人提供）：血管痉挛是蛛网膜下腔出血（SAH）患者延迟缺血性中风的常见原因。 在这个项目中，我们将评估负责引起SAH诱导的大脑血管痉挛的分子。 血管痉挛的原因在很大程度上尚不清楚，但有人建议是由于出血性CSF中的血管活性分子。 我们发现，在SAH患者的CSF中发现了胆红素氧化产物（盒子），并建议这些盒子是磷酸酶抑制剂，可引起脑血管痉挛。 已经确定了三个与结构相关的分子。 这些分子会对体内和体外的血管产生长时间的收缩作用，这与血管痉挛患者CSF的长时间血管痉挛非常相似。 我们建议平滑肌蛋白磷酸酶抑制会导致长时间的血管痉挛。 此外，正是磷酸酶抑制剂的盒子在蛛网膜下腔出血后会产生长时间的血管痉挛。 在使用颅窗技术的目标＃1和＃2中，我们将检查由盒子引起的大鼠脑血管痉挛的时间过程，并将评估单个盒子的效力。血管收缩程度将在14天内研究，并检查大脑是否有损害的证据。 在AIM＃3中，我们将表明盒子抑制磷酸酶，并且在体外使用猪基底动脉导致血管痉挛。 该项目的长期目标是确定血管痉挛的分子原因（例如胆红素氧化产物，磷酸酶抑制），以开发有效的诊断性，治疗性和预防性方法来为这种脑血管疾病采用。