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Mechanisms underlying dampened ischemic tolerance in type 2 diabetes

2 型糖尿病缺血耐受减弱的机制

基本信息

批准号：
10620176
负责人：
JIALING LIU
金额：
--
依托单位：
VETERANS AFFAIRS MED CTR SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620176
关键词：
Affect Age Aging Agonist Anti-Inflammatory Agents Attenuated Biological Assay Blood Vessels Blood flow Cells Cerebral Ischemia Chronic Coagulation Process Compensation Data Defect Exposure to Extravasation Failure Gene Expression Genes Goals Heterogeneity Hour Human Image Immune Immune response Immunosuppression Infarction Inflammation Interferon-beta Interferons Ischemia Ischemic Brain Injury Ischemic Preconditioning Ischemic Stroke Knowledge Leptomeninges Leukocyte Trafficking Leukocytes Link Mediating Meningeal Meninges Metabolic Diseases Methods Microcirculatory Bed Molecular Mus Myeloid Cells Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Obesity Optical Coherence Tomography Organ Paper Pathologic Peripheral Pharmaceutical Preparations Phenotype Population Reporting Research Resistance Resistance development Signal Pathway Signal Transduction Stimulus Stroke T-Cell Proliferation Testing Therapeutic Therapeutic Intervention Thrombelastography Thrombus Time Tissues Toll-like receptors Vascular blood supply Velocimetries brain cell brain parenchyma clinical application comparison control conditioning db/db mouse diabetic immunoregulation improved innate immune pathways insight ischemic injury monocyte neurobehavior neuroprotection peripheral blood pharmacologic post stroke preconditioning response sex single-cell RNA sequencing stroke outcome technology platform therapeutic target transcriptome

项目摘要

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.

对脑缺血的耐受性可以通过暴露于短暂的缺血或药物，包括 Toll 样受体 (TLR) 激动剂，这是一种已知的现象作为缺血预适应（IPC）。已有证据表明先天免疫 TLR 和 1 型干扰素 (IFN) 信号传导等途径参与 IPC 介导神经保护。尽管众所周知，对缺血的耐受性或 IPC 的作用随着年龄和病理状况（包括代谢性疾病）而下降，潜在的这种阻尼效应的机制尚不清楚。使用单细胞 RNA 测序，我们最近发现T2DM小鼠db/db外周血中的单核细胞 1 型和 2 型 IFN 信号通路有缺陷，导致它们无法产生已知具有免疫调节和抗-干扰素刺激基因（ISG）炎症。鉴于 db/db 小鼠中存在缺陷的干扰素反应的前提，我们假设他们应该表现出对脑缺血的耐受性减弱 TLR 介导的预处理与 db/+ 小鼠的比较。为了检验假设，我们将比较 TLR 激动剂 CpG 或 LPS 预处理对 T2DM 小鼠和对照小鼠的影响通过卒中结果、血流成像、凝血来评估 MCAO。我们将确定 TLR-的效果介导白细胞向脑膜和脑实质运输的预处理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反应如何使它们倾向于发布与中风相比，中风免疫抑制加剧血管损伤和血脑屏障渗漏控制老鼠。本研究中获得的知识对于识别潜力将具有深刻的洞察力规避年龄和代谢疾病相关的缺血性下降的治疗目标多个器官的耐受性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice.

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

Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy.