靶向钠钾ATP酶治疗缺血性脑卒中的抗体研发及机制研究

Stroke is a central nervous system disease with high morbidity, disability and mortality. Though progress has been made in pathologic mechanisms of stroke in animal experiments, there is no effective drug available for patients except recombinant tissue plasminogen activator (rtPA) approved by the United States food and drug administration (FDA). The Na+/K+-ATPase (NKA) (also known as “sodium-potassium pump”) is a ubiquitous and critically important protein complex in all mammalians. It is a P-type ion transporter consisting of a heterodimeric core of α and β subunits that may be accompanied by a third γ subunit. Recent studies show that NKA plays an important role in ischemic stroke, but the mechanisms are not elucidated. In this project, we aim to: 1) clarify the role of NKA in the neuronal damages caused by ischemic insults. NKAα1, NKAα2 and NKAα3 heterozygous mice will be used in tMCAO model to investigate the dysfunction of NKA in ischemic stroke; 2) develop anti-NKA antibodies (NKA-Abs) to active NKA. DR-region antigen, HN-region antigen and RD-region antigen of NKA will be used to develop NKA antibodies to active NKA; 3) investigate the effects of NKA-Abs in ischemic stroke and elucidate the underlying mechanisms. The effects of NKA-Abs will be evaluated by in vivo (tMCAO) and in vitro experiments (OGD/R), and the protective mechanisms will be focused on excitotoxicity and oxidative stress. The present study will not only reveal a novel sight of NKA in ischemic stroke, but also provide a new therapeutic target for drug development for the treatment of ischemic stroke.

脑卒中是一类高发病率、高致残率和高致死率的中枢神经系统疾病，其临床治疗药物的研究进展缓慢。目前除rtPA外，仍无有效的急性期治疗药物可用。钠钾ATP酶（NKA）是一种广泛表达于所有动物细胞质膜上的P型离子转运ATP酶，由α、β和γ三种亚基组成。研究发现，NKA与缺血性脑卒中神经损伤密切相关，然而其具体机制尚未清楚。本项研究首先应用NKAα1、α2和α3敲减小鼠制备缺血性脑卒中模型，着重于阐明α亚基不同亚型对缺血性脑卒中神经损伤的影响；其次研发针对于NKA不同区域的抗体DR-Ab、HN-Ab和RD-Ab，研究激动NKA对缺血性脑卒中的保护作用，并进一步制备兴奋性毒性损伤模型和氧化应激模型，阐明NKA抗体发挥缺血性脑卒中神经保护作用的具体机制。本研究结果不仅阐明了NKA与缺血性脑卒中神经损伤的相关性及具体机制，而且为缺血性脑卒中的药物研发提供了新靶点，开拓了缺血性脑卒中免疫治疗的新策略。

脑卒中是一类高发病率、高致残率和高致死率的中枢神经系统疾病，其临床治疗药物的研究进展缓慢。目前除rtPA外，仍无有效的急性期治疗药物可用。钠钾ATP酶（NKA）是一种广泛表达于所有动物细胞质膜上的P型离子转运ATP酶，由α、β和γ三种亚基组成。研究发现，NKA与缺血性脑卒中神经损伤密切相关，然而其具体机制尚未清楚。本项研究首先应用NKAα1、α2和α3敲减小鼠制备缺血性脑卒中模型，着重于阐明α亚基不同亚型对缺血性脑卒中神经损伤的影响；其次研发针对于NKA不同区域的抗体DR-Ab、HN-Ab和RD-Ab，研究激动NKA对缺血性脑卒中的保护作用，并进一步制备兴奋性毒性损伤模型和氧化应激模型，阐明NKA抗体发挥缺血性脑卒中神经保护作用的具体机制。本研究结果不仅阐明了NKA与缺血性脑卒中神经损伤的相关性及具体机制，而且为缺血性脑卒中的药物研发提供了新靶点，开拓了缺血性脑卒中免疫治疗的新策略。