Macrophages, Cell-Cell Communication, Ischemic Injury in Diabetes and the RAGE/DIAPH1 Signaling Axis

巨噬细胞、细胞间通讯、糖尿病缺血性损伤和 RAGE/DIAPH1 信号轴

基本信息

项目摘要

Project Summary: OVERALL Ischemia, a complication of diabetic cardiovascular (CVD) and peripheral arterial disease (PAD), is accompanied by the recruitment, infiltration and activation of monocytes/macrophages (MΦs), into affected tissues. In diabetes, MΦ properties are perturbed and repair is significantly mitigated, leading to organ failure. The microenvironments in the heart vs. the skeletal muscle display unique responses to ischemia, but the mechanisms are not fully understood. The ligands of the receptor for advanced glycation endproducts (RAGE), such as nonenzymatically glycated and oxidized advanced glycation endproducts; S100/calgranulins and high mobility group box 1, which accumulate in non-diabetic and diabetic CVD and PAD tissue, and RAGE itself, contribute to MΦ and niche-specific responses to ischemia. Mice globally devoid of Ager (the gene encoding RAGE) or devoid of myeloid Ager (lethal irradiation/bone marrow transplantation) are protected from the adverse effects of ligation of the left anterior descending coronary artery and the femoral artery, models for myocardial infarction (MI) and hind limb ischemia (HLI), respectively. In MI and HLI models, Ager deletion is accompanied by a marked reduction in tissue MΦ content and reduced expression of inflammatory mediators. Surprisingly, in HLI, deletion of Ager is accompanied by increased MΦ content and expression of inflammatory mediators in the skeletal muscle. Yet, in both cases, Ager deletion augured repair. Our discovery that the cytoplasmic domain of RAGE interaction with the formin, DIAPH1, mediates signal transduction, generation of oxidative stress and mitochondrial dysfunction (on account of our novel discovery that DIAPH1 binds to Mitofusin2 (MFN2) in ischemic tissue MΦs, cardiomyocytes and endothelial cells), may hold the key to these RAGE-dependent findings. The three Projects of this Program will use novel mouse models, state-of-the-art molecular biology techniques, novel small molecule antagonists of RAGE-DIAPH1 interaction, NMR spectroscopy and in-cell fluorescence assays to test the hypothesis that RAGE/DIAPH1 contributes to MΦ cell-intrinsic and MΦ- cardiomyocyte cross talk in MI and to and MΦ-endothelial cell cross talk in HLI, thereby amplifying tissue damage. We posit that RAGE-DIAPH1 and DIAPH1-MFN2 interactions control MΦ inflammation and that pharmacological blockade of RAGE-DIAPH1-MFN2 interaction and/or administration of monocytes/MΦs devoid of Ager or Diaph1 will facilitate the transition from pro-injury to adaptive MΦ inflammation and, thereby, hasten tissue repair in the diabetic heart and peripheral arterial systems. The meticulous integration of in vivo biology and molecular mechanisms studies (Projects 1 and 2) with structural biology (Project 3) assures the innovation, significance and ultimate relevance of this work for the development of novel therapeutic strategies for diabetes and ischemia.
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项目成果

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ANN MARIE SCHMIDT其他文献

ANN MARIE SCHMIDT的其他文献

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{{ truncateString('ANN MARIE SCHMIDT', 18)}}的其他基金

Macrophages, Cell-Cell Communication, Ischemic Injury in Diabetes and the RAGE/DIAPH1 Signaling Axis
巨噬细胞、细胞间通讯、糖尿病缺血性损伤和 RAGE/DIAPH1 信号轴
  • 批准号:
    10191018
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Project 2: Diabetes, RAGE/DIAPH1 and Hind Limb Ischemia
项目2:糖尿病、RAGE/DIAPH1 和后肢缺血
  • 批准号:
    10191022
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10642705
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10191019
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10407555
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Project 2: Diabetes, RAGE/DIAPH1 and Hind Limb Ischemia
项目2:糖尿病、RAGE/DIAPH1 和后肢缺血
  • 批准号:
    10407558
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Macrophages, Cell-Cell Communication, Ischemic Injury in Diabetes and the RAGE/DIAPH1 Signaling Axis
巨噬细胞、细胞间通讯、糖尿病缺血性损伤和 RAGE/DIAPH1 信号轴
  • 批准号:
    10642704
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
Project 2: Diabetes, RAGE/DIAPH1 and Hind Limb Ischemia
项目2:糖尿病、RAGE/DIAPH1 和后肢缺血
  • 批准号:
    10642712
  • 财政年份:
    2019
  • 资助金额:
    $ 248.03万
  • 项目类别:
RAGE, DIAPH1 and IRF7 and Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Disease
动脉粥样硬化和心脏代谢疾病中的 RAGE、DIAPH1 和 IRF7 以及巨噬细胞功能障碍
  • 批准号:
    10424906
  • 财政年份:
    2017
  • 资助金额:
    $ 248.03万
  • 项目类别:
Mouse Breeding and Procedure Core
小鼠育种和程序核心
  • 批准号:
    10616534
  • 财政年份:
    2017
  • 资助金额:
    $ 248.03万
  • 项目类别:

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