人尿激肽原酶对缺血区脑灌注的影响和机制研究

Ischemic stroke is one of the leadingcauses of disability and fatality in China，which has no satisfactory conventional treatment strategies available to date. Promoting angiogenesis，which can increase cerebral blood flow in the ischemic zone correspondingly，has became a conspicuous research direction in the area of cerebrovascular disease recently. Our preliminary studies demonstrated that HUK could improve the neurological deficit in the ischemic stroke rats and suppress inflammation induced by brain infarction. We also found HUK could increase glucose metabolism and local cerebral blood flow in the cerebral ischemic rabbits. In addition, we demonstrated HUK could increase the density of microvessel in ischemia penumbral zone through immunofluorescence. On the basis of our preliminary studies, we will continue the study by basic animal research in vivo(MCAO model) and in vitro(human umbilical vein endothelial cells cultivation ) via the techniques of pathology 、molecular biology and fMRI，on the following three aspects:1)to demonstrate the effect on cerebral perfusion of HUK in ischemic zone and the correlation between perfusion and neurological function; 2) to demonstrate HUK can affect cerebral perfusion by promoting neovascularization and the correlation between time as well as dosage of HUK and vascularization;3) to investigate the underlying mechanisms of HUK to promote neovascularization. We aim to to find a new target and approach for the treatment of ischemic stroke through our research.

缺血性卒中是造成我国居民致残、致死的重要原因之一，治疗措施有限。近年来，促进血管生成从而增加缺血区脑灌注成为脑血管病领域倍受瞩目的研究方向。我们的前期研究发现①人尿激肽原酶（HUK）明显改善缺血性卒中小鼠的神经功能，抑制缺血诱导的炎症损伤②HUK增加兔脑缺血后局部葡萄糖代谢和局部脑血流量，免疫荧光结果显示HUK增加缺血半暗区微血管密度③HUK能改善急性脑梗死患者神经功能缺损，增加缺血区脑灌注。本课题在前期工作的基础上，旨在通过动物在体研究（MCAO模型）、离体研究（血管生成模型），利用病理学、分子生物学、功能磁共振等技术，进一步从以下三个方面研究：1）证实HUK对缺血区脑灌注的影响，以及与神经功能的相关性；2）证实HUK通过促血管生成影响脑灌注，HUK治疗时间和剂量与灌注和血管生成的相关性；3）明确HUK促血管生成的分子调控机制。其结果为缺血性卒中的治疗寻找新的靶点和治疗思路。

缺血性卒中是造成我国居民致残、致死的重要原因之一，治疗措施有限。近年来，促进血管生成从而增加缺血区脑灌注成为脑血管病领域倍受瞩目的研究方向。我们前期工作研究发现①人尿激肽原酶（HUK）明显改善缺血性卒中小鼠的神经功能，抑制缺血诱导的炎症损伤②HUK增加兔脑缺血后局部葡萄糖代谢和局部脑血流量，免疫荧光结果显示HUK增加缺血半暗区微血管密度。为了明确HUK治疗脑梗死的作用机制，在这些前期工作的基础上，我们通过临床研究发现HUK能改善急性脑梗死患者临床预后，减少致残率，对血压等无明显影响。MRP扫描发现HUK干预后脑梗死患者缺血区血供明显增加，外周血VEGF和 apelin/APJ表达增加。18F-FDG micro-PET 扫描显示HUK能增加MCAO鼠的血流灌注。组织病理学研究发现HUK能增加局部新生血管密度，并且上调了VEGF和apelin/APJ 的表达。在细胞层面研究中发现，HUK能上调内皮细胞模型VEGF和apelin/APJ的表达，激活ERK1/2信号传导通路。以上研究，从临床到基础全方位揭示了HUK治疗急性脑梗死的机制，开拓了侧枝循环改善研究的视野。