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
基本信息
- 批准号:10624293
- 负责人:
- 金额:$ 60.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAcuteAgeAnimal ModelAtherosclerosisAttenuatedBindingBinding SitesBloodBlood PlateletsBrainBrain EdemaBrain InfarctionBrain InjuriesBrain IschemiaCASP3 geneCaspaseCerebral IschemiaComplications of Diabetes MellitusDeteriorationDevelopmentDoseEIF-2alphaFemaleGenesGoalsGuidelinesHemorrhageHippocampusHourHyperglycemiaHyperlipidemiaImmunosuppressionIndividualIndustryInfectionInflammatory ResponseInjuryIntravenousIschemiaIschemic StrokeLifeMediatingMicroRNAsModelingMolecularMolecular Mechanisms of ActionMolecular TargetMusNeurologicNeurologic DeficitNeuronal InjuryNeuronsOlder PopulationOligonucleotidesPathologicPathologic ProcessesPatientsPlasminogen Activator Inhibitor 1Recovery of FunctionRegulationReperfusion InjuryReperfusion TherapyRoleSafetySecondary toStrokeTestingTherapeuticTherapeutic EffectTherapeutic InterventionTimeUpdateacute strokeage relatedagedanimal mortalitycerebral microvasculaturecombatdesigneffective interventionefficacy evaluationefficacy testingendoplasmic reticulum stressexperimental studygain of functionhigh riskin vivoinnovationintravenous injectionloss of functionmalenervous system disorderneuron apoptosisneuron lossnovelnovel therapeutic interventionpost strokepre-clinicalpreventresponsestroke riskstroke therapytherapeutic miRNAthromboinflammationthrombolysisthrombotictreatment and outcomeyoung adult
项目摘要
Project Summary/Abstract
The cerebral ischemia/reperfusion (I/R) injury is a major challenge for the treatment of patients with acute
ischemic stroke by intravenous (IV) thrombolysis and endovascular therapy. Currently, there is no effective
intervention available to treat/prevent cerebral I/R injury. Emerging evidence suggests that thrombotic and
inflammatory responses (thrombo-inflammation) and aberrant endoplasmic reticulum (ER) stress in the brain
elicited by cerebral I/R contributes importantly to secondary brain injury and neurologic deterioration. In this
proposal we wish to develop a novel miRNA-based therapeutic strategy to simultaneously target these
pathological processes of cerebral I/R injury through distinct molecular mechanisms. Recently, decreased
expression of miR-30c has been implicated in many pathological conditions in both patients and animal models.
In preliminary studies, we show that miR-30c is highly expressed in blood platelets, cerebral microvessels, and
cortical/hippocampal neurons in normal mice but its levels decline with age. miR-30c levels in both blood and
brain are markedly decreased after ischemic stroke and elevating miR-30c by single IV injection of synthetic
miR-30c mimic significantly protects against cerebral I/R injury. We further show that the increased expressions
of the direct target genes of miR-30c (including PAI-1 in both blood and brain, elF2α and caspase-3 in the brain)
induced by cerebral I/R injury were significantly decreased by IV miR-30c mimic treatment. Based on these
exciting new findings from young adult mice, we propose the innovative hypothesis that miR-30c functions as a
critical regulator of thrombo-inflammation and ER stress in the ischemic brain elicited by cerebral I/R injury, and
thus targeting miR-30c represents a novel therapeutic approach for combating cerebral I/R injury. Following
updated stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines, we will test this
hypothesis in aged male and female mice. Specifically, we will determine the efficacy and safety of IV miR-30c
mimic as novel stroke therapeutics (Aim1). Using complementary approaches, i.e. the “gain-of-function” (miR-
30c mimic) and “loss-of-function” (anti-sense Morpholino oligos that are designed to specifically compete with
miR-30c for binding sites of 3’UTR of each individual target gene and thus acts as a “target protector”), we will
identify PAI-1 as a key molecular target of miR-30c in regulation of post-stroke thrombo-inflammation (Aim 2),
and identify elF2α and caspase 3 as key molecular targets of miR-30c in regulation of post-stroke neuronal ER
stress and neuronal cell death (Aim 3). The long-term goal of these studies is to evaluate if targeting miR-30c is
a viable option for stroke therapy in both male and female older populations at high risk for stroke.
项目总结/摘要
脑缺血/再灌注(I/R)损伤是急性脑梗死患者治疗的主要挑战
通过静脉(IV)溶栓和血管内治疗缺血性卒中。目前,没有有效的
可用于治疗/预防脑I/R损伤的干预。新出现的证据表明,血栓性和
炎症反应(血栓-炎症)和异常内质网(ER)应激
脑I/R诱发的脑缺血再灌注损伤是继发性脑损伤和神经功能恶化的重要原因。在这
我们希望开发一种新的基于miRNA的治疗策略,同时靶向这些
脑I/R损伤的病理过程通过不同的分子机制。最近,减少
在患者和动物模型中,miR-30 c的表达与许多病理状况有关。
在初步研究中,我们发现miR-30 c在血小板、脑微血管和脑胶质细胞中高度表达。
皮质/海马神经元中,但其水平随年龄而下降。血液和血液中的miR-30 c水平
脑缺血性卒中后显著降低,并通过单次IV注射合成的
miR-30 c模拟物显著保护脑I/R损伤。我们进一步表明,增加的表达
miR-30 c的直接靶基因(包括血液和脑中的派-1,脑中的eIF 2 α和caspase-3)
通过IV miR-30 c模拟物处理显著降低了由脑I/R损伤诱导的脑缺血再灌注损伤。基于这些
我们从年轻成年小鼠中获得了令人兴奋的新发现,我们提出了一个创新的假设,即miR-30 c的功能是
脑I/R损伤引起的缺血性脑中血栓炎症和ER应激的关键调节剂,和
因此,靶向miR-30 c代表了对抗脑I/R损伤的新的治疗方法。以下
更新的卒中治疗学术行业圆桌会议(STAIR)临床前指南,我们将对此进行测试
老年雄性和雌性小鼠的假设。具体而言,我们将确定IV miR-30 c的有效性和安全性。
模拟为新型中风治疗剂(Aim 1)。使用互补方法,即“功能获得性”(miR-125),
30 c模拟物)和“功能丧失”(设计为特异性竞争30 c模拟物的反义吗啉代寡核苷酸)。
miR-30 c用于每个单独靶基因的3 'UTR的结合位点,因此充当“靶保护剂”),我们将
鉴定派-1作为miR-30 c调节卒中后血栓炎症的关键分子靶点(目的2),
并确定eIF 2 α和caspase 3是miR-30 c调节卒中后神经元ER的关键分子靶点
应激和神经元细胞死亡(目的3)。这些研究的长期目标是评估靶向miR-30 c是否
在中风高危的男性和女性老年人群中中风治疗的可行选择。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Blocking of PI3-kinase beta protects against cerebral ischemia/reperfusion injury by reducing platelet activation and downstream microvascular thrombosis in rats.
- DOI:10.1038/s41598-023-29235-2
- 发表时间:2023-02-04
- 期刊:
- 影响因子:4.6
- 作者:
- 通讯作者:
J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats.
- DOI:10.3389/fneur.2022.821082
- 发表时间:2022
- 期刊:
- 影响因子:3.4
- 作者:Jin R;Wang M;Zhong W;Kissinger CR;Villafranca JE;Li G
- 通讯作者:Li G
Emerging Role of MicroRNA-30c in Neurological Disorders.
MicroRNA-30c 在神经系统疾病中的新作用
- DOI:10.3390/ijms24010037
- 发表时间:2022-12-20
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
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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
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 - 财政年份:2023
- 资助金额:
$ 60.17万 - 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:
10297340 - 财政年份:2021
- 资助金额:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 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:
$ 60.17万 - 项目类别:
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