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
- 来源:
- 关键词:AD transgenic miceAcuteAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloidAmyloid beta-ProteinBrainBrain InjuriesBrain IschemiaClinical ResearchCognitiveCognitive deficitsDataDepositionDown-RegulationDrug Delivery SystemsEarly treatmentFDA approvedGene ExpressionHippocampusHourHumanImpaired cognitionImpairmentInfarctionInjuryIntranasal AdministrationIntravenousIschemic Brain InjuryIschemic StrokeKnockout MiceLinkMicroRNAsMiddle Cerebral Artery OcclusionMolecular TargetMusNeurologicNeurologic DeficitNeuronsOutcomePathologyPatientsPhasePlayProteinsQuality of lifeRecombinantsRecoveryRegulationRegulator GenesReperfusion TherapyRoleSecondary toSerumSmall Interfering RNAStrokeSynaptic plasticityTestingTherapeuticTherapeutic EffectTimeTissuesUntranslated RegionsWild Type Mouseacute strokeagedbeta amyloid pathologybrain tissuecognitive functioncognitive recoverydisabilityefficacy evaluationendoplasmic reticulum stressexperienceexperimental studygain of functionhippocampal pyramidal neuronimprovedinhibitorintravenous administrationloss of functionmouse modelneuropathologynew therapeutic targetnovelnovel therapeutic interventionpost strokepost stroke cognitive impairmentpost stroke dementiareconstitutionstroke cognitive outcomestroke modelstroke patientstroke survivortherapeutic targetthrombolysisyoung 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。
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:
7910679 - 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:
7527030 - 财政年份:2008
- 资助金额:
$ 66.82万 - 项目类别:
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