A New Molecular Target to Enhance Poststroke Cognitive Recovery

增强中风后认知恢复的新分子靶点

• 批准号: 10658539
• 负责人: Guohong Li
• 金额: $ 66.82万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658539
• 关键词: AD transgenic mice; Acute; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Brain; Brain Injuries; Brain Ischemia; Clinical Research; Cognitive; Cognitive deficits; Data; Deposition; Down-Regulation; Drug Delivery Systems; Early treatment; FDA approved; Gene Expression; Hippocampus; Hour; Human; Impaired cognition; Impairment; Infarction; Injury; Intranasal Administration; Intravenous; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Link; MicroRNAs; Middle Cerebral Artery Occlusion; Molecular Target; Mus; Neurologic; Neurologic Deficit; Neurons; Outcome; Pathology; Patients; Phase; Play; Proteins; Quality of life; Recombinants; Recovery; Regulation; Regulator Genes; Reperfusion Therapy; Role; Secondary to; Serum; Small Interfering RNA; Stroke; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Untranslated Regions; Wild Type Mouse; acute stroke; aged; beta amyloid pathology; brain tissue; cognitive function; cognitive recovery; disability; efficacy evaluation; endoplasmic reticulum stress; experience; experimental study; gain of function; hippocampal pyramidal neuron; improved; inhibitor; intravenous administration; loss of function; mouse model; neuropathology; new therapeutic target; novel; novel therapeutic intervention; post stroke; post stroke cognitive impairment; post stroke dementia; reconstitution; stroke cognitive outcome; stroke model; stroke patient; stroke survivor; therapeutic target; thrombolysis; young adult

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.

项目摘要 中风是美国和世界范围内长期残疾的主要原因。脑卒中后认知功能障碍 卒中后脊髓损伤（PSCI）是卒中后常见的后遗症，是卒中幸存者生活质量的决定性因素。 临床研究表明，PSCI在年轻和老年脑卒中患者中都很常见，即使在某些情况下， 相对轻度卒中和成功溶栓和血管内再灌注治疗的患者。 然而，对PSCI的潜在机制仍然知之甚少，并且没有FDA批准的治疗方法。 可用于PSCI。在本申请中，我们建议研究的作用和治疗潜力， DKK 3在PSCI中的表达及其机制研究 脑动脉闭塞（MCAO）后再灌注。以前的研究（包括我们的研究） 研究表明，短暂性MCAO的小鼠出现了长期的认知缺陷， 海马体有继发性损伤基于我们有希望的试点数据，我们假设DKK 3 不仅在急性脑损伤中起重要作用，而且在继发性海马损伤中也起重要作用， 因此代表了一种新的有希望的治疗靶点，用于治疗缺血性脑损伤后的认知障碍， 中风首先，我们将确定DKK 3（和miR-125 a）表达的时空调控， 脑卒中后不同时间点正常脑和缺血脑，并评价早期治疗的疗效 与通过鼻内施用重组DKK 3蛋白以改善急性胰腺炎的延迟治疗相比， 卒中损伤和改善缺血性卒中后的长期神经和认知结局（Aim 1）。 接下来，我们将确定DKK 3在神经病理学中的机制作用，重点是海马 缺血性卒中后PSCI的机制（目的2）。为了验证这一假设，功能丧失和增益- 将进行功能丧失实验，其中常规和条件性DKK 3敲除小鼠和 将利用重组DKK 3通过鼻内药物递送的功能重建研究。基于 基于初步数据，我们进一步假设缺血性卒中诱导miR-125 a表达增加， 下调海马中DKK 3的表达，这有助于短暂性脑缺血诱导的PSCI。 MCAO（目标3）。我们将确定miR-125 a抑制对改善PSCI的DKK 3依赖性作用。 在缺血性中风之后。将研究年轻成年小鼠和老年小鼠。拟议的研究可能揭示 PSCI的潜在机制，并提供了一种新的治疗方法， 改善缺血性卒中后神经功能和认知结果。