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Mechanisms underlying dampened ischemic tolerance in type 2 diabetes

Mechanisms underlying dampened ischemic tolerance in type 2 diabetes
2 型糖尿病缺血耐受减弱的机制
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

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中文摘要
翻译
对脑缺血的耐受性可以通过暴露于短暂的缺血或 包括Toll样受体(TLR)激动剂的药理学试剂,这是已知的现象, 缺血预处理(IPC)。已有证据表明先天免疫 诸如TLR和1型干扰素(IFN)信号传导的途径参与IPC介导的 神经保护虽然众所周知,缺血耐受或IPC的作用 随着年龄的增长和病理条件,包括代谢疾病,基础 这种阻尼效应的机理还不清楚。使用单细胞RNA测序, 我们最近发现,T2 DM小鼠db/db外周血中的单核细胞 1型和2型IFN信号通路缺陷,使其不能产生 干扰素刺激基因(ISG),已知是免疫调节和抗- 煽动性鉴于db/db小鼠中IFN反应缺陷的前提,我们 假设它们应该表现出对脑缺血减弱耐受性, TLR介导的预处理与db/+小鼠相比。为了检验假设,我们将比较 TLR激动剂CpG或LPS预处理对T2 DM和对照小鼠的影响 根据卒中结局、血流成像、凝血功能确定MCAO。我们将确定TLR的效果- 介导的预处理对白细胞向脑膜和脑实质运输的影响 比较每个隔室中白细胞的表型和转录组谱。我们将 还确定db/db小鼠中改变的天然免疫应答如何使它们易于后 中风免疫抑制和加重血管损伤和血脑屏障渗漏相比, 对照小鼠。在这项研究中获得的知识将有助于确定潜在的 治疗目标,以规避年龄和代谢疾病相关的缺血性脑卒中的下降, 多器官耐受性。
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)
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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
ShEEP request for High Performance Electrophysiological System for Recording and Closed-Loop Stimulation
BLR&D Research Career Scientist Award Application
BLR&D Research Career Scientist Award Application
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