Activin A介导的短时程抗脑缺血损伤信号环路作用机制研究

发布时间：2019-04-17 12:03

【摘要】：脑局部血流中断或减少所致的神经细胞缺血损伤是脑梗死的主要病理生理基础。在其干预手段中,血管再通治疗已成为目前临床的主要策略之一。但因受时间窗及血运重建率等的限制,血管再通干预策略目前仅有少数患者受益。包括接受血管再通治疗在内的大部分患者仍需要依赖于组织、细胞水平的抗损伤干预以减轻神经功能缺损。因此,基于可逆损伤时程之内的神经保护策略仍然是国内外基础研究领域的一个热点问题。激活素A(Activin A,Act A),作为转化生长因子β(transforming growth factor-β,TGF-β)超家族的成员之一,在急性缺血性脑损伤早期表达上调,并通过Act A/Smads通路发挥神经保护功能。在体外模拟的脑缺血性损伤氧糖剥夺(oxygen-glucose deprivation,OGD)模型中,课题组前期研究发现,与既往研究不同,Act A/Smads信号从细胞外到细胞内的传导过程可能并非呈单方向的线性转导。针对前期研究结果提示可能存在的Act A/Smads信号环路,本研究利用基因克隆技术构建Act A重组载体,稳定转染后建立Act A高表达的PC12细胞系,利用Act A基因高表达及细胞外积累模拟缺血损伤介导的Act A通路活化过程,对Act A/Smads信号活化、放大及衰竭机制及可能干预靶点进行了研究,取得如下结果:(1)Act A基因表达上调及细胞外积累可引发Act A/Smads正反馈环路活化,活化过程具有Act A细胞外浓度梯度依赖性;(2)Act A/Smads环路在短时程激活后进入衰竭状态,呈现一定的自限性;(3)受Act A环路自限性影响,其在缺血性脑损伤中的神经保护作用有限;(4)Smad锚着蛋白(Smad anchor for receptor activation,SARA)表达水平调控Act A/Smads环路信号强度,可作为放大Act A抗缺血性损伤功能的潜在干预靶点。
[Abstract]:The main pathophysiological basis of cerebral infarction is the neuronal ischemia injury caused by the interruption or decrease of cerebral blood flow. Among the intervention methods, recanalization therapy has become one of the main clinical strategies. However, due to the limitation of time window and revascularization rate, only a few patients benefit from vascular recanalization intervention. Most patients, including recanalization, still rely on tissue and cell-level anti-injury interventions to reduce neurological deficits. Therefore, the neural protection strategy based on reversible damage duration is still a hot issue in the field of basic research at home and abroad. Act A), a member of the transforming growth factor 尾 (transforming growth factor- 尾 (TGF- 尾) superfamily, is up-regulated in the early stage of acute ischemic brain injury and plays a neuroprotective role through the Act A/Smads pathway. Activin A is a member of the transforming growth factor 尾 (transforming growth factor- 尾 (TGF- 尾) superfamily. In the oxygen-glucose deprivation (oxygen-glucose deprivation,OGD) model of cerebral ischemic injury simulated in vitro, the previous study of our team found that, in contrast to previous studies, The transduction process of Act A/Smads signal from extracellular to intracellular may not be linear transduction in one direction. In view of the possible existence of Act A/Smads signal loop, the recombinant vector of Act-A was constructed by gene cloning technique. After stable transfection, a PC12 cell line with high expression of Act-A was established. Using the high expression of Act A gene and extracellular accumulation to simulate the activation of Act A pathway mediated by ischemia injury, the mechanism of Act A/Smads signal activation, amplification and failure and the possible targets of intervention were studied. The results are as follows: (1) up-regulation of) Act A gene expression and extracellular accumulation can induce the activation of positive feedback loop of Act A/Smads, and the activation process is dependent on the extracellular concentration gradient of Act-A; (2) the Act A/Smads loop entered a state of failure after short-term activation, showing a certain degree of self-limitation; (3) the neuroprotective effect of Act-A loop was limited in ischemic brain injury; (4) the expression level of Smad anchor protein (Smad anchor for receptor activation,SARA can regulate the signal intensity of Act A/Smads loop, which can be used as a potential intervention target for amplifying the anti-ischemic damage function of Act A.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R743.3

【相似文献】