腺苷激酶在远隔后处理诱介导缺血脑保护的作用机制研究

Remote postconditioning (RPostC) arouses endogenous protection against ischemia, enhances ischemia tolerance of brain tissue. Compared with preconditioning, the timing of postconditioning is more easily controlled, thus the clinical translation of remote postconditioning is more reasonable. However, the mechanism under remote postconditioning is still with unknown, which suppresses this potential therapy strategy from bench to bedside. We have found that, adenosine kinase (ADK) was increased after brain injury, which subsequently induced neuronal death; and remote postconditioning can suppress the overexpression of adenosine kinase after cerebral ischemia. Combined with the results of previous research, we hypothesized that adenosine kinase took part in the brain protection of remote postconditioning. This project will start with the expression, location and catalytic activity changes of adenosine kinase, and will investigate the molecular mechanism of neuron protection exerted by adenosine kinase, and will finally demonstrate whether adenosine kinase was the key molecular regulator of remote postconditioning. With this project, we hope to find theory support for clinical translation of remote postconditoining, and to find new pharmaceutic target of brain protection against cerebral ischemia.

远隔后处理能激活内源性缺血保护，提高脑组织缺血耐受；且由于后处理的干预时机可控，较预处理更具临床转化价值。然而，远隔后处理的作用机制不清，使这一潜在治疗方法的临床转化缺乏足够的理论依据。课题组前期研究发现腺苷激酶在脑损伤后反应性表达增加，并能介导神经损伤；而远隔后处理能抑制缺血所导致的脑内腺苷激酶高表达；结合前人对腺苷激酶的研究成果，我们推测其可能参与调控远隔后处理的缺血脑保护作用。本课题从检测腺苷激酶的表达、定位及催化活性改变入手，对其在远隔后处理缺血脑保护中的效应及机制进行深入探讨，并证实其是否为远隔后处理缺血脑保护的关键调控分子，为远隔后处理的临床转化提供理论支持，并为脑保护药物研究提供新的可能的干预靶点。

远隔后处理具有内源性脑保护作用，具有较强的临床转化价值。然而，远隔后处理缺血脑保护作用机制不清，是其临床转化的瓶颈。课题组通过整体水平研究，证实远隔后处理能抑制缺血性脑损伤所致的ADK表达增加；同时，通过对ADK活性测定，课题组发现远隔后处理能抑制中枢ADK活性，提高外周肌肉ADK活性。在细胞模型中，课题组发现后处理过程中，HIF-1α对ADK造成了负向调控，下调HIF-1α表达使ADK表达上调，进而加重细胞缺氧损伤，提示HIF-1α在ADK分子机制中发挥重要作用。最终，课题组通过抑制ADK活性或整体水平敲减ADK表达，证实了其为调控远隔后处理脑保护的关键调控分子，为远隔后处理的临床转化提供理论支持，并为脑保护药物研究提供新的可能的干预靶点。