Adenosine kinase as therapeutic target to induce and maintain ischemic tolerance

描述（由申请人提供）：急性脑损伤可导致神经保护和对后续损伤的耐受。然而，这种内源性神经保护的机制还不完全清楚。由于急性癫痫发作后腺苷的增加既具有神经保护作用又具有抗癫痫作用，因此腺苷还可在缺血中提供神经保护和耐受性。急性癫痫发作后腺苷水平升高是由于腺苷代谢的关键酶腺苷激酶（ADK）下调所致。因此，腺苷- ADK系统可能是一种内源性耐受效应物.我们的目的是研究ADK是如何调节缺血性脑损伤的反应，以及这些发现如何转化为应用，以防止损伤的大脑。这些研究的基本原理来自于我们实验室以前的以下发现：（1）ADK作为对损伤性癫痫发作和短暂局灶性脑缺血的急性反应而迅速和短暂地下调。(2)ADK的上调使大脑更容易受到缺血性细胞损失的影响。(3)纹状体内植入腺苷释放干细胞可保护大脑免受随后的缺血。(4)药物阻断或RNAi介导的ADK下调可有效抑制癫痫发作和癫痫诱导的损伤。我们的中心假设是，损伤后ADK的急性和短暂下调是损伤的一种普遍现象，并负责诱导缺血耐受，并且这种有益ADK反应的增强和延长具有神经保护作用。我们将研究ADK在啮齿动物缺血模型中的表达。在治疗方法中，将通过慢病毒RNAi抑制ADK表达来诱导缺血耐受。该项目的具体目标是：目标1。研究腺苷系统在诱导缺血耐受中的作用。目标2.通过治疗性下调ADK诱导耐受。公共卫生相关性：我们计划研究预防中风后细胞丢失的新机制和策略。在治疗上，增强脑的内源性神经保护性腺苷系统有望诱导对缺血性脑损伤的耐受性。我们的研究结果可能会转化为有效的新疗法，用于预防中风后的脑损伤。

DESCRIPTION (provided by applicant): Acute brain injury can result in neuroprotection and tolerance to subsequent injury. However, the mechanisms of this endogenous neuroprotection are incompletely known. As the increase in adenosine following acute seizures is both neuroprotective and antiepileptic, adenosine may also provide neuroprotection and tolerance in ischemia. The elevation of adenosine following acute seizures is due to downregulation of adenosine kinase (ADK), the key enzyme of adenosine metabolism. Thus, the adenosine- ADK system may be a candidate as an endogenous tolerance effector. We aim to investigate how ADK is regulated in response to ischemic brain injury and how these findings can be translated into applications to prevent damage to the injured brain. The rationale for these studies is derived from the following previous findings from our lab: (1) ADK is rapidly and transiently downregulated as an acute response to both injurious seizures and transient focal cerebral ischemia. (2) Upregulation of ADK renders the brain more vulnerable to ischemic cell loss. (3) Intrastriatal implants of adenosine releasing stem cells protect the brain from subsequent ischemia. (4) Pharmacological blockade or RNAi-mediated downregulation of ADK effectively suppress seizures and seizure-induced injury. Our CENTRAL HYPOTHESIS is that the acute and transient downregulation of ADK after an insult is a general phenomenon of injury and responsible for the induction of ischemic tolerance and that augmentation and prolongation of this beneficial ADK-response is neuroprotective. We will investigate ADK expression in rodent models of ischemia. In a therapeutic approach ischemic tolerance will be induced by inhibiting ADK expression by lentiviral RNAi. The SPECIFIC AIMS of this project are: Aim 1. Study the involvement of the adenosine system in the induction of ischemic tolerance. Aim 2. Induce tolerance by therapeutic downregulation of ADK. PUBLIC HEALTH RELEVANCE: We plan to investigate novel mechanisms and strategies to prevent cell loss after stroke. Therapeutically, augmentation of the brain's endogenous neuroprotective adenosine system is expected to induce tolerance to ischemic brain injury. Our findings may be translated into effective new therapies for the prevention of brain damage after stroke.