A New Molecular Target to Enhance Poststroke Cognitive Recovery

项目总结 在美国和世界范围内，中风是导致长期残疾的主要原因。卒中后认知障碍 卒中后常见后遗症(PSCI)是卒中幸存者生活质量的决定性决定因素。 临床研究表明，PSCI在年轻和老年中风患者中都很常见，甚至在 相对轻度中风和成功进行血管内溶栓和血管内再灌注治疗的患者。 然而，PSCI的潜在机制仍然知之甚少，也没有FDA批准的治疗方法 适用于PSCI。在这一应用中，我们建议研究其作用和治疗潜力。 短暂性中枢性卒中模型中PSCI中DKK3的表达及其机制 脑动脉闭塞(MCAO)后再灌流。之前的研究(包括我们的研究)已经 证明了受到短暂性大脑中动脉闭塞的小鼠会发展出长期的认知缺陷 并对海马体造成二次损伤。基于我们有希望的试验数据，我们假设DKK3 不仅在急性脑损伤中起重要作用，而且在继发性海马区损伤中也发挥重要作用 为治疗脑缺血后认知功能障碍提供了一个新的治疗靶点 卒中。首先，我们将确定DKK3(和miR-125a)在小鼠体内表达的时空调节。 卒中后不同时间点的正常和缺血脑组织，并评价早期治疗的效果 重组DKK3蛋白鼻腔给药缓解急性呼吸窘迫综合征 并改善缺血性中风后的长期神经学和认知结果(Aim1)。 接下来，我们将确定DKK3在神经病理学中的机制作用，重点是在海马区 缺血性卒中后PSCI的机制(目标2)。为了检验这一假设，功能损失和增益- 将进行功能实验，其中常规和条件DKK3基因敲除小鼠和 将利用通过鼻腔给药的重组DKK3进行功能重建研究。基座 根据试点数据，我们进一步假设缺血性中风导致miR-125a表达增加，因此 下调DKK3在海马区的表达，参与短暂性脑损伤的发生 MCAO(目标3)。我们将确定抑制miR-125a改善PSCI的DKK3依赖效应 缺血性卒中后。年轻的成年和老年的小鼠都将被研究。拟议的研究可能会揭示 并提供了一种新的治疗方法 改善缺血性中风后的神经学和认知结果。

PROJECT SUMMARY Stroke is a leading cause of long-term disability in U.S. and worldwide. Post-stroke cognitive impairment (PSCI), a common sequela after stroke, is a decisive determinant of the quality of life for stroke survivors. Clinical studies have indicated that PSCI is common in both young and old stroke patients, even in cases of relative mild stroke and victims with successful thrombolysis and endovascular reperfusion therapies. However, the underlying mechanisms of PSCI remains poorly understood and no FDA approved treatment is available for PSCI. In this application, we propose to investigate the roles and therapeutic potential of DKK3 in PSCI and the underlying mechanisms using an experimental stroke model of transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Previous studies (including ours) have demonstrated that mice subjected to transient MCAO developed long-term cognitive deficits that correlate with secondary damage to the hippocampus. Based on our promising pilot data, we hypothesize that DKK3 plays an important role not only in acute brain damage but also in secondary hippocampal damage and thereby represents a novel promising therapeutic target for treating cognitive impairment after ischemic stroke. First, we will determine the tempo-spatial regulation of DKK3 (and miR-125a) expression in the normal and ischemic brains at different time points after stroke, and evaluate the efficacy of early treatment versus delayed treatment by intranasal administration of recombinant DKK3 protein to ameliorate acute stroke injury and to improve long-term neurologic and cognitive outcomes after ischemic stroke (Aim1). Next, we will determine the mechanistic roles of DKK3 in neuropathology with the focus on the hippocampal mechanisms of PSCI after ischemic stroke (Aim 2). To test this hypothesis, the loss-of-function and gain- of-function experiments will be performed, in which conventional and conditional DKK3 knockout mice and functional reconstitution study with recombinant DKK3 via intranasal drug delivery will be utilized. Based on pilot data, we further hypothesize that ischemic stroke induces increase of miR-125a expression hence down-regulates DKK3 expression in the hippocampus, which contributes to PSCI induced by transient MCAO (Aim 3). We will determine the DKK3-dependent effects of miR-125a inhibition to improve PSCI after ischemic stroke. Both young adult and aged mice will be studied. The proposed studies may reveal previously unappreciated mechanisms underlying PSCI and provide a novel therapeutic approach to improve neurologic and cognitive outcomes following ischemic stroke.