COBRE: UVM MED PROJ 5: CEREBRAL VASOSPASM MECHANISM IN SUBARACHNOID HEMORRHAGE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。动脉瘤破裂和蛛网膜下腔出血（SAH）后的脑血管痉挛是一种毁灭性的疾病，每年造成数千人残疾和死亡。目前，关于这种血液诱导的脑动脉狭窄的细胞机制知之甚少。也许我们已经报道了增强压力诱导的收缩小直径脑动脉从兔模型的蛛网膜下腔出血。 我们目前的工作表明，Ca 2+信号和电压依赖性Ca 2+通道（VDCC）特性的根本变化导致这种增强的脑动脉收缩。我们最近发表的研究（Ishiguro等人，Circ.结果：2005）首次证明了血管痉挛期间脑动脉中新型“R型”钙通道（由基因CaV 2.3编码）的表达。我们认为，R型钙通道有助于增强脑动脉瘤破裂后的收缩，并可能代表一个新的治疗目标，在治疗与血管痉挛相关的神经功能缺损。我们的初步数据还表明，氧合血红蛋白（一种与血管痉挛有关的血液成分）可以降低电压依赖性钾（KV）通道活性，从而通过膜电位去极化间接增加VDCC活性。在接下来的一年里，我们将集中精力探索与蛛网膜下腔出血相关的Ca 2+通道表达变化的机制。此外，我们将继续与Moreilli博士合作研究氧合血红蛋白诱导的钾通道抑制。这项工作应显着提高目前的知识方面的Ca 2+信号和收缩脑动脉的健康和疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cerebral vasospasm following aneurysm rupture and subarachnoid hemorrhage (SAH) is a devastating disorder that inflicts disability and death upon thousands of individuals each year. Currently, little is known regarding the cellular mechanisms of this blood-induced cerebral artery narrowing. Peviously we have reported enhanced pressure-induced constriction in small diameter cerebral arteries obtained from a rabbit model of subarachnoid hemorrhage. Our current work indicates that fundamental changes in Ca2+ signaling and voltage-dependent Ca2+ channel (VDCC) properties leads to this enhanced constriction of cerebral arteries. Our recently published study (Ishiguro et al., Circ. Res., 2005) demonstrates, for the first time, the expression of a novel "R-type" calcium channel (encoded by the gene CaV 2.3) in cerebral arteries during vasospasm. We propose that R-type calcium channels contribute to enhanced cerebral artery constriction following aneurysm rupture and may represent a novel therapeutic target in the treatment of neurological deficits associated with vasospasm. Our preliminary data also suggests oxyhemoglobin, a blood component linked to vasospasm, decreases voltage-dependent potassium (KV) channel activity to indirectly increase VDCC activity via membrane potential depolarization. In the upcoming year we will focus our efforts on exploring mechanisms involved in changes in Ca2+ channel expression associated with subarachnoid hemorrhage. Also we will continue our collaboration with Dr. Moreilli examining oxyhemogobin-induced potassium channel suppression. This work should significantly enhance current knowledge with respect to Ca2+ signaling and constriction of cerebral arteries in health and disease.