A New Molecular Target to Enhance Poststroke Cognitive Recovery

增强中风后认知恢复的新分子靶点

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要中风是美国和全世界长期残疾的主要原因。中风后认知障碍（PSCI）是中风后常见的后遗症，是中风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，甚至在病例中也是如此相对轻度中风和成功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，并且 FDA 还没有批准治疗方法适用于 PSCI。在此应用中，我们建议研究以下药物的作用和治疗潜力： PSCI 中的 DKK3 及其使用短暂中风实验模型的潜在机制脑动脉闭塞（MCAO），然后再灌注。以前的研究（包括我们的）已经证明接受短暂 MCAO 的小鼠会出现长期认知缺陷，这与海马体继发性损伤。根据我们有希望的试点数据，我们假设 DKK3 不仅在急性脑损伤中发挥重要作用，而且在继发性海马损伤和因此代表了治疗缺血后认知障碍的新的有前景的治疗靶点中风。首先，我们将确定 DKK3（和 miR-125a）表达的时空调节脑卒中后不同时间点的正常大脑和缺血大脑，并评估早期治疗的效果与鼻内给予重组 DKK3 蛋白延迟治疗以改善急性中风损伤并改善缺血性中风后的长期神经和认知结果（目标1）。接下来，我们将确定 DKK3 在神经病理学中的机制作用，重点关注海马缺血性卒中后 PSCI 的机制（目标 2）。为了检验这个假设，功能丧失和增益将进行功能丧失实验，其中常规和条件性 DKK3 敲除小鼠和将利用通过鼻内药物递送重组 DKK3 的功能重建研究。基于根据试点数据，我们进一步假设缺血性中风会诱导 miR-125a 表达增加，因此下调海马中 DKK3 的表达，这有助于短暂性诱发的 PSCI MCAO（目标 3）。我们将确定 miR-125a 抑制的 DKK3 依赖性效应以改善 PSCI 缺血性中风后。年轻的成年小鼠和老年小鼠都将被研究。拟议的研究可能会揭示以前未被认识到的 PSCI 潜在机制，并提供了一种新的治疗方法改善缺血性中风后的神经系统和认知结果。