Mechanisms underlying dampened ischemic tolerance in type 2 diabetes
Mechanisms underlying dampened ischemic tolerance in type 2 diabetes
批准号:
10620176
负责人:
JIALING LIU
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-07-01 至 2025-03-31
关键词:
AffectAgeAgingAgonistAnti-Inflammatory AgentsAttenuatedBiological AssayBlood VesselsBlood flowCellsCerebral IschemiaChronicCoagulation ProcessCompensationDataDefectExposure toExtravasationFailureGene ExpressionGenesGoalsHeterogeneityHourHumanImageImmuneImmune responseImmunosuppressionInfarctionInflammationInterferon-betaInterferonsIschemiaIschemic Brain InjuryIschemic PreconditioningIschemic StrokeKnowledgeLeptomeningesLeukocyte TraffickingLeukocytesLinkMediatingMeningealMeningesMetabolic DiseasesMethodsMicrocirculatory BedMolecularMusMyeloid CellsNatural ImmunityNon-Insulin-Dependent Diabetes MellitusObesityOptical Coherence TomographyOrganPaperPathologicPeripheralPharmaceutical PreparationsPhenotypePopulationReportingResearchResistanceResistance developmentSignal PathwaySignal TransductionStimulusStrokeT-Cell ProliferationTestingTherapeuticTherapeutic InterventionThrombelastographyThrombusTimeTissuesToll-like receptorsVascular blood supplyVelocimetriesbrain cellbrain parenchymaclinical applicationcomparison controlconditioningdb/db mousediabeticimmunoregulationimprovedinnate immune pathwaysinsightischemic injurymonocyteneurobehaviorneuroprotectionperipheral bloodpharmacologicpost strokepreconditioningresponsesexsingle-cell RNA sequencingstroke outcometechnology platformtherapeutic targettranscriptome
中文摘要
对脑缺血的耐受性可通过暴露于短暂的缺血或
包括Toll样受体(TLR)激动剂在内的药物,这是一种已知的现象
作为缺血预适应(IPC)。确凿的证据表明,先天免疫
TLRs和1型干扰素信号转导通路参与IPC介导
神经保护。尽管众所周知,对缺血的耐受性或缺血预适应的影响
随着年龄和包括代谢性疾病在内的病理条件的下降,潜在的
这种减震效应的机理还不是很清楚。使用单细胞RNA测序,
我们最近发现T2 DM小鼠外周血中的单核细胞是
1型和2型干扰素信号通路缺陷,导致它们不能产生
干扰素刺激基因(ISGs)是已知的免疫调节和抗
煽动性的。假设db/db小鼠的干扰素反应有缺陷,我们
假设他们应该表现出对脑缺血的耐受性减弱
TLR介导的预适应与db/小鼠的比较。为了检验假设,我们将比较
TLR激动剂CpG或脂多糖预适应对T2 DM及正常小鼠的影响
MCAO按卒中转归、血流显像、凝血等指标判定。我们将确定TLR的影响-
介导的预适应对白细胞向脑膜和脑实质转运的影响
比较各隔室白细胞的表型和转录组图谱。我们会
还要确定db/db小鼠体内改变的天然免疫反应如何使它们易于后继。
卒中免疫抑制和加重血管损伤和血脑屏障渗漏
控制小鼠。在这项研究中获得的知识将对发现潜力有很大帮助
规避年龄和代谢性疾病相关缺血性疾病下降的治疗目标
多器官的耐受性。
英文摘要
Tolerance to cerebral ischemia can be induced by exposure to brief ischemia or
pharmacological agents including the Toll-like receptor (TLR) agonists, a phenomenon known
as the ischemic preconditioning (IPC). Established evidence suggests that innate immune
pathways such as TLRs and type 1 interferon (IFN) signaling are involved in IPC-mediated
neuroprotection. Although it is well known that tolerance to ischemia or the effect of IPC
declines with age and pathological conditions including metabolic diseases, the underlying
mechanism for this damping effect is not well understood. Using single cell RNA sequencing,
we have recently found that monocytes in the peripheral blood of T2DM mice db/db are
defective in type 1 and type 2 IFN signaling pathways, rendering them incapable of producing
interferon stimulus genes (ISGs) that are known to be immunomodulatory and anti-
inflammatory. Given the premise of the defective IFN responses in the db/db mice, we
hypothesize that they should show attenuated tolerance against cerebral ischemia following
TLR-mediated preconditioning compared to db/+ mice. To test hypothesis, we will compare the
effect of preconditioning with TLR agonists CpG or LPS in T2DM and control mice subjected to
MCAO by stroke outcome, blood flow imaging, coagulation. We will determine the effect of TLR-
mediated preconditioning on leukocyte trafficking to the meninges and brain parenchyma by
comparing phenotypes and transcriptome profile of leukocytes in each compartment. We will
also determine how the altered native immune responses in db/db mice predispose them to post
stroke immunosuppression and exacerbated vascular damage and BBB leakage compared to
control mice. The knowledge gained in this study will be insightful in identifying potential
therapeutic targets to circumvent age and metabolic disease-associated decline in ischemic
tolerance in multiple organs.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1161/strokeaha.116.014882
发表时间:
2016-12
期刊:
Stroke
影响因子:
8.3
作者:
[Nishijima Y, Akamatsu Y, Yang SY, Lee CC, Baran U, Song S, Wang RK, Tominaga T, Liu J]
通讯作者:
Liu J
DOI:
10.3390/ijms161025605
发表时间:
2015-10-26
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Rabiller G, He JW, Nishijima Y, Wong A, Liu J]
通讯作者:
Liu J
DOI:
10.1016/j.bbr.2016.09.013
发表时间:
2018-03-15
期刊:
Behavioural brain research
影响因子:
2.7
作者:
[Neumann M, Liu W, Sun C, Yang SY, Noble-Haeusslein LJ, Liu J]
通讯作者:
Liu J
Analysis of stroke-induced changes in connectivity and neural activity
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批准号:10309635
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项目类别:
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资助金额:$44.41万
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财政年份:2021
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负责人:JIALING LIU
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依托单位:
ShEEP request for High Performance Electrophysiological System for Recording and Closed-Loop Stimulation
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批准号:9906728
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项目类别:
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资助金额:$0.0万
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负责人:JIALING LIU
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BLR&D Research Career Scientist Award Application
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资助金额:$0.0万
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依托单位:
BLR&D Research Career Scientist Award Application
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资助金额:$0.0万
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依托单位:
BLR&D Research Career Scientist Award Application
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批准号:9911967
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依托单位:
BLR&D Research Career Scientist Award Application
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Stroke in females with metabolic syndrome, a vascular perspective
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项目类别:
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负责人:JIALING LIU
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Stroke in females with metabolic syndrome, a vascular perspective
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Collateral flow and stroke outcome
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负责人:JIALING LIU
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Collateral flow and stroke outcome
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依托单位:
Mechanisms underlying dampened ischemic tolerance in type 2 diabetes
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批准号:10405532
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项目类别:
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资助金额:$0.0万
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财政年份:2016
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负责人:JIALING LIU
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依托单位:
Mechanisms underlying dampened ischemic tolerance in type 2 diabetes
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批准号:10255350
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项目类别:
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资助金额:$0.0万
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Mechanisms underlying Netrin-1-mediated functional recovery after stroke
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负责人:JIALING LIU
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依托单位:
Mechanisms underlying Netrin-1-mediated functional recovery after stroke
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资助金额:$0.0万
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负责人:JIALING LIU
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依托单位:
Mechanisms underlying Netrin-1-mediated functional recovery after stroke
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项目类别:
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资助金额:$0.0万
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财政年份:2012
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负责人:JIALING LIU
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依托单位:
Mechanisms underlying Netrin-1-mediated functional recovery after stroke
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批准号:8840075
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项目类别:
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资助金额:$0.0万
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负责人:JIALING LIU
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Neuroplasticity after experimental stroke
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Neuroplasticity after experimental stroke
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Neuroplasticity after experimental stroke
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