Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

摘要： 在美国，中风仍然是导致残疾的主要原因。中风是一种异质的多因素 无序。先前开发新疗法的尝试由于靶标验证不完善而在临床上失败， 不现实的治疗窗口和缺乏适合年龄的模型。因此，有机会也有需要。 寻找治疗中风的新药物。免疫细胞移动到大脑中的中风区域，并对 去破坏。我们最近发现，腺苷过度刺激了嘌呤能的P2X4受体 中风时垂死的脑细胞释放的三磷酸(ATP)。这种受体蛋白然后导致激活 免疫细胞和导致更大的中风伤害。我们已经组装了必要的工具，如动物 缺乏P2X4受体以及选择性抑制该受体的阻滞剂。这项提议，使用这些新的 工具，旨在调查这种受体蛋白是否是开发治疗慢性阻塞性肺疾病患者的新靶点 卒中。我们的初步数据表明，在中风急性期阻断或删除这种受体蛋白是 有益的。然而，目前还不清楚这种蛋白质是如何发挥作用的，以及它可能产生的潜在不利影响。 回答这些问题是这里的总目标，应该确定追求新的 中风治疗

Summary: Stroke remains a leading cause of disability in the United States. Stroke is a heterogeneous multifactorial disorder. Prior attempts at developing new therapies have failed in clinics due to imperfect target validation, unrealistic therapeutic windows and lack of age appropriate models. Thus, there is an opportunity and a need to identify new medical treatment for stroke. The immune cells move to stroke area in the brain and contribute to damage. We have recently shown that the purinergic P2X4 receptor is excessively stimulated by adenosine triphosphate (ATP) released by dying brain cells during stroke. This receptor protein then causes activation of the immune cells and results in greater stroke injury. We have assembled the necessary tools such as animals lacking P2X4 receptors as well as blockers that selectively inhibit the receptor. The proposal, using these new tools, aims to investigate whether this receptor protein is a novel target to develop treatment for subjects with stroke. Our initial data suggest that blocking or deleting this receptor protein during the acute phase of stroke is beneficial. However, it is unknown how this protein works and what its potential adverse effects might be. Answering these questions is the overall goal here and should define the correct approach in pursuing a new stroke treatment