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:
  • 金额:
    $ 66.82万
  • 依托单位:
  • 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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Guohong Li其他文献

Guohong Li的其他文献

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{{ truncateString('Guohong Li', 18)}}的其他基金

Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury
脑缺血再灌注损伤的新靶点和治疗干预措施
  • 批准号:
    10297340
  • 财政年份:
    2021
  • 资助金额:
    $ 66.82万
  • 项目类别:
Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury
脑缺血再灌注损伤的新靶点和治疗干预措施
  • 批准号:
    10624293
  • 财政年份:
    2021
  • 资助金额:
    $ 66.82万
  • 项目类别:
Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury
脑缺血再灌注损伤的新靶点和治疗干预措施
  • 批准号:
    10414999
  • 财政年份:
    2021
  • 资助金额:
    $ 66.82万
  • 项目类别:
Therapeutic Targeting of the Class IB PI3-Kinase Gamma for Treatment of Acute Ischemic Stroke
IB 类 PI3 激酶 Gamma 的治疗靶向治疗急性缺血性中风
  • 批准号:
    9344701
  • 财政年份:
    2016
  • 资助金额:
    $ 66.82万
  • 项目类别:
Therapeutic Targeting of the Class IB PI3-Kinase Gamma for Treatment of Acute Ischemic Stroke
IB 类 PI3 激酶 Gamma 的治疗靶向治疗急性缺血性中风
  • 批准号:
    9318030
  • 财政年份:
    2016
  • 资助金额:
    $ 66.82万
  • 项目类别:
The Role of CD147 in Ischemic Inflammation and Brain Injury
CD147 在缺血性炎症和脑损伤中的作用
  • 批准号:
    9348678
  • 财政年份:
    2016
  • 资助金额:
    $ 66.82万
  • 项目类别:
The role of CD147 in ischemic inflammation and brain injury
CD147在缺血性炎症和脑损伤中的作用
  • 批准号:
    8767043
  • 财政年份:
    2014
  • 资助金额:
    $ 66.82万
  • 项目类别:
The role of CD147 in ischemic inflammation and brain injury
CD147在缺血性炎症和脑损伤中的作用
  • 批准号:
    8877660
  • 财政年份:
    2014
  • 资助金额:
    $ 66.82万
  • 项目类别:
Mechanisms of CD40/CD40L in vascular injury and repair
CD40/CD40L在血管损伤与修复中的机制
  • 批准号:
    7527030
  • 财政年份:
    2008
  • 资助金额:
    $ 66.82万
  • 项目类别:
Mechanisms of CD40/CD40L in vascular injury and repair
CD40/CD40L在血管损伤与修复中的机制
  • 批准号:
    7910679
  • 财政年份:
    2008
  • 资助金额:
    $ 66.82万
  • 项目类别:

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