Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
基本信息
- 批准号:10221785
- 负责人:
- 金额:$ 32.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AlteplaseAnabolismAstrocytesBehavior assessmentBehavioralBioinformaticsBrainCell Culture TechniquesCell DeathCell SurvivalCellsCerebral IschemiaClinical ResearchComputer softwareDNA RepairDataDevelopmentDocosahexaenoic AcidsDoseExperimental ModelsFosteringFutureGene ClusterGenesGlucoseGlutamatesGoalsHomeostasisInfarctionInflammationInterventionIschemiaIschemic Brain InjuryIschemic PenumbraIschemic StrokeKnockout MiceKnowledgeLinkLongevityMagnetic Resonance ImagingMediatingMediator of activation proteinMicrofluidicsMolecularMolecular GeneticsN-Methyl-D-Aspartate ReceptorsNervous system structureNeurologicNeurologic DeficitNeuronsOmega-3 Fatty AcidsOutputOxygenPathway AnalysisPhenotypePlayPolymersPropertyProteinsRattusRecoveryReperfusion TherapyRing Finger DomainRoleSignal PathwaySignal TransductionStressStrokeTestingTherapeuticUp-RegulationWestern BlottingWorkagedcell motilitycerebral ischemic injurydeprivationeffective therapyembolic strokeexcitotoxicitygenetic signatureimprovedlipid mediatornerve stem cellneuroblastneurogenesisneuroinflammationneuron apoptosisneuroprotectin D1neuroprotectionneurorestorationneurotrophic factorpost strokerecruitresponserestorationstem cellsstroke modelstroke outcomestroke therapythromboembolic strokethrombolysistranslational impact
项目摘要
PROJECT SUMMARY / ABSTRACT
Although neuroprotective strategies have shown promise, no treatment has demonstrated efficacy after stroke.
This project focuses on the neuroprotective bioactivity of docosanoid (DOC) mediators: Neuroprotectin D1
(NPD1), Resolvin D1 (RvD1), and their combination (NPD1+RvD1) against ischemic and embolic experimental
stroke. These lipid mediators are biosynthesized “on demand” in response to the onset of stroke to resolve
neuroinflammation and restore homeostasis. Our preliminary studies show that administration of NPD1 after
OGD in neuronal cell cultures modifies clusters of genes and upstream potential master regulators that decrease
neuronal apoptosis and neuroinflammation, improve cell homeostasis, and that beneficially impact genes
expressed in ischemia-reperfusion. In addition, we show that DOC provide neurological/behavioral recovery,
reduce infarct size, increase neurogenesis, and promote cell survival after ischemic stroke. The overall goal of
our studies is to uncover a mechanistic understanding of DOC action in MCAo. Our central hypothesis is that
DOC foster neuronal and astrocyte integrity by targeting selective gene clusters preceding neuronal protection
and by the homeostatic signaling integration regulated by the mesencephalic astrocyte-derived neurotrophic
factor (MANF) and by the ring finger protein 146 (Iduna). Specific aim 1 will test the hypothesis that DOC regulate
pro-homeostatic and cell survival bioactivity after MCAo by modulating specific gene clusters. We will define the
doses and therapeutic window, as well as their effect on the ischemic penumbra and we will define whether the
lipid mediators are neuroprotective in embolic stroke with or without tissue plasminogen activator of thrombolysis.
We selected genes from our data on neuronal cultures, including, some encoding lncRNAs, and propose to
define by RT-qPCR high-throughput microfluidics workflow their expression after MCAo with and without DOC.
Specific aim 2 will test the hypothesis that MANF and Iduna enhanced abundance by DOC integrates
homeostatic signaling restoration and proliferation of neural stem cells leading to neuroprotection. Both are pro-
survival proteins that target different neuroprotective mechanisms. Since NPD1 biosynthesis is stimulated by
neurotrophins, we will explore the relationship DHA→DOC (NPD1, RvD1 and NPD1+RvD1) →MANF→Iduna→
protection by unfolded protein response pro-survival signaling outputs. A DOC or combinations will outline
outputs of the unfolded protein response driven by MANF and Iduna. Since ischemic stroke engages
UPR signaling we will define lncRNAs as regulators and effectors of UPR that fine-tune the output of
the stress signaling pathways and identify also which specific gene signatures are MANF and or Iduna
dependent. The scientific premise of the proposed studies is that identification of the most effective DOC or
combination of DOC to target gene clusters necessary for neuroprotection/neurorestoration modulated by the
lipid mediators which will provide the basis for future clinical studies on potential interventions to reduce the
immediate and long-term consequences of stroke.
项目总结/摘要
虽然神经保护策略已经显示出希望,但没有治疗在中风后表现出有效性。
本项目的重点是神经保护生物活性的docosanoid(DOC)介质:神经保护素D1
(NPD 1)、Resolvin D1(RvD 1)和它们的组合(NPD 1 + RvD 1)抗缺血性和栓塞性实验
中风这些脂质介质是生物合成的“需求”,以应对中风的发作,以解决
神经炎症和恢复稳态。我们的初步研究表明,NPD 1的管理后,
神经元细胞培养物中的OGD改变了基因簇和上游潜在的主调节因子,
神经元凋亡和神经炎症,改善细胞稳态,并有益地影响基因
在缺血再灌注中表达。此外,我们表明,DOC提供神经/行为恢复,
减少梗死面积,增加神经发生,促进缺血性卒中后细胞存活。的总目标
我们的研究旨在揭示DOC在MCAo中作用的机理。我们的核心假设是,
DOC通过在神经元保护之前靶向选择性基因簇促进神经元和星形胶质细胞的完整性
以及中脑星形胶质细胞源性神经营养因子调节的稳态信号整合
环指蛋白146(Iduna)。具体目标1将检验DOC调节
通过调节特定的基因簇,在MCAo后具有促稳态和细胞存活的生物活性。我们将定义
剂量和治疗窗,以及它们对缺血半暗带的影响,我们将确定是否
脂质介质在有或没有组织纤溶酶原激活剂溶栓的栓塞性卒中中具有神经保护作用。
我们从神经元培养的数据中选择了基因,包括一些编码lncRNA的基因,并提出
通过RT-qPCR高通量微流体工作流程定义它们在有和没有DOC的MCAo后的表达。
具体目标2将检验MANF和Iduna通过DOC整合提高丰度的假设
稳态信号传导恢复和神经干细胞增殖导致神经保护。两者都是亲--
针对不同神经保护机制的生存蛋白。由于NPD 1的生物合成受到
神经营养因子,我们将探讨DHA→DOC(NPD 1,RvD 1和NPD 1 + RvD 1)→MANF→Iduna→
通过未折叠的蛋白质应答促存活信号输出进行保护。DOC或组合将概述
由MANF和Iduna驱动的未折叠蛋白质响应的输出。由于缺血性中风
我们将lncRNA定义为UPR的调节因子和效应因子,
应激信号通路,并鉴定哪些特定基因标记是MANF和/或Iduna
依赖。拟议研究的科学前提是,确定最有效的DOC或
DOC与靶向基因簇的组合,这些基因簇是由神经保护/神经恢复调节所必需的
脂质介质,这将为未来的潜在干预措施,以减少临床研究的基础。
中风的直接和长期后果。
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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Nicolas G. Bazan其他文献
Localization of lipocalin-type prostaglandin D synthase (beta-trace) in iris, ciliary body, and eye fluids.
脂质运载蛋白型前列腺素 D 合酶(β-痕量)在虹膜、睫状体和眼液中的定位。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:4.4
- 作者:
D. Gerashchenko;C. T. Beuckmann;V. Marcheselli;William C. Gordon;Y. Kanaoka;Naomi Egucbi;Y. Urade;O. Hayaishi;Nicolas G. Bazan - 通讯作者:
Nicolas G. Bazan
Diffusion of intracerebrally injected [1-14C]arachidonic acid and [2-3H]Glycerol in the mouse brain
- DOI:
10.1007/bf00965088 - 发表时间:
1982-12-01 - 期刊:
- 影响因子:3.800
- 作者:
Maria F. Pediconi;Elena B. Rodriguez de Turco;Nicolas G. Bazan - 通讯作者:
Nicolas G. Bazan
The Optimization of a Natural Language Processing Approach for the Automatic Detection of Alzheimer’s Disease Using GPT Embeddings
使用 GPT 嵌入优化自动检测阿尔茨海默病的自然语言处理方法
- DOI:
10.3390/brainsci14030211 - 发表时间:
2024 - 期刊:
- 影响因子:3.3
- 作者:
Benjamin S. Runde;Ajit Alapati;Nicolas G. Bazan - 通讯作者:
Nicolas G. Bazan
Composition and metabolism of phospholipids during earyly stages of vertebrate embryonic development.
脊椎动物胚胎发育早期阶段磷脂的组成和代谢。
- DOI:
10.1007/978-1-4684-3276-3_23 - 发表时间:
1977 - 期刊:
- 影响因子:0
- 作者:
A. M. P. D. D’Angelo;I. C. B. D. Romanelli;Telma S. Alonso;Nicolas G. Bazan - 通讯作者:
Nicolas G. Bazan
Regulation of arachidonic acid metabolism in the perinatal brain during development and under ischemic stress.
发育期间和缺血应激下围产期大脑花生四烯酸代谢的调节。
- DOI:
- 发表时间:
1992 - 期刊:
- 影响因子:0
- 作者:
E. Yavin;B. Kunievsky;Nicolas G. Bazan;Shaul Harel - 通讯作者:
Shaul Harel
Nicolas G. Bazan的其他文献
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{{ truncateString('Nicolas G. Bazan', 18)}}的其他基金
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
- 批准号:
10395594 - 财政年份:2019
- 资助金额:
$ 32.87万 - 项目类别:
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
- 批准号:
10606600 - 财政年份:2019
- 资助金额:
$ 32.87万 - 项目类别:
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
- 批准号:
9815688 - 财政年份:2019
- 资助金额:
$ 32.87万 - 项目类别:
Novel combinatory therapy for experimental ischemic stroke
实验性缺血性中风的新型组合疗法
- 批准号:
10330435 - 财政年份:2018
- 资助金额:
$ 32.87万 - 项目类别:
Novel combinatory therapy for experimental ischemic stroke
实验性缺血性中风的新型组合疗法
- 批准号:
10093153 - 财政年份:2018
- 资助金额:
$ 32.87万 - 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
- 批准号:
8853292 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
- 批准号:
9068162 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
- 批准号:
8668105 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
- 批准号:
8536885 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
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