Bone Marrow Neuropathy Drives Diabetic Retinopathy

骨髓神经病变导致糖尿病视网膜病变

基本信息

项目摘要

DESCRIPTION (provided by applicant): In the previous funding period, we demonstrated that diabetic individuals and mice demonstrate dysfunctional endothelial progenitor cells. These bone marrow (BM) derived cells are released into the circulation in an abnormal manner due to diabetes-induced BM neuropathy. This BM neuropathy leads to dysregulation in the circadian release of these cells into the circulation. These BM changes precede development of diabetic retinopathy (DR) linking BM neuropathy for the first time to DR. Diabetic BM supernatants, but not control, contain high levels of monocyte/macrophage-colony stimulating factor (M-CSF) and diabetic mice exhibit an increase number of monocytes in the retina and circulation. Based on these findings, we hypothesize that: Diabetic BM denervation initiates HSC/progenitor dysfunction that leads to an increase in total monocytes generated, this, coupled with increased expression of CCL2 (monocyte chemoattractent protein-1) by retinal glia results in excessive levels of the pro-inflammatory (M1) monocytes in the diabetic retina. In addition, diminished levels of CX3CL1 (fractalkine) expression by dysfunctional neurons heightens the inflammatory response of resident microglia. This imbalance leads to a neural inflammation that accelerates DR pathogenesis. We will test this hypothesis both in vitro and in vivo through the simultaneous exploration of the following aims: Aim 1: To determine whether diabetes induced BM neuropathy is responsible for increased M-CSF production by BM stromal cells which shifts hematopoiesis towards generation of excessive numbers of monocytes, in particular pro-inflammatory Gr1+/CCR2+/CX3CR1lo monocytes, rather than the protective Gr1-/CCR2-/CX3CR1hi monocytes. Aim 2: To determine the roles of CCL2 and CX3CL1 in DR inflammation and to test whether restoration of the balance of CCR2+CX3CR1lo and CCR2-/CX3CR1hi monocytes and simultaneous restoration of levels of endothelial progenitors to retinal vasculature will prevent o reverse DR in T1D mice. Aim 3: Our hypothesis predicts that circulating pro- inflammatory Gr1+/CCR2+i/CX3CR1lo cells will cause endothelial cell activation, promote leukostasis and result in enhanced retinal permeability whereas Gr1-/CCR2-/CX3CR1hi cells will protect the BRB in diabetes. We will examine the effects of manipulating these subsets on the progression of DR. Targeting monocyte subtypes may represent an ideal strategy for DR prevention and treatment. CellMax?
描述(由申请人提供):在之前的资助期内,我们证明糖尿病个体和小鼠显示内皮祖细胞功能失调。由于糖尿病诱导的骨髓神经病变,这些骨髓来源的细胞以一种异常的方式释放到循环中。这种BM神经病变导致这些细胞进入循环的昼夜节律释放失调。这些BM变化先于糖尿病视网膜病变(DR)的发展,首次将BM神经病变与DR联系起来。糖尿病BM上清,而不是对照,含有高水平的单核细胞/巨噬细胞集落刺激因子(M-CSF),糖尿病小鼠的视网膜和循环中单核细胞数量增加。基于这些发现,我们假设:糖尿病BM断神经引发HSC/祖细胞功能障碍,导致总单核细胞产生增加,再加上视网膜胶质细胞CCL2(单核细胞趋化蛋白-1)表达增加,导致糖尿病视网膜中促炎(M1)单核细胞水平过高。此外,功能失调神经元CX3CL1 (fractalkine)表达水平的降低会增强驻留小胶质细胞的炎症反应。这种不平衡导致神经炎症,加速DR发病。我们将在体外和体内通过同时探索以下目标来验证这一假设:目的1:确定糖尿病诱导的BM神经病变是否导致BM基质细胞产生M-CSF增加,从而使造血功能转向产生过多的单核细胞,特别是促炎的Gr1+/CCR2+/CX3CR1lo单核细胞,而不是保护性的Gr1-/CCR2-/CX3CR1hi单核细胞。目的2:确定CCL2和CX3CL1在DR炎症中的作用,并测试恢复CCR2+CX3CR1lo和CCR2-/CX3CR1hi单核细胞的平衡,同时恢复视网膜血管内皮祖细胞的水平,是否可以预防或逆转T1D小鼠的DR。目的3:我们的假设预测循环促炎性Gr1+/CCR2+i/CX3CR1lo细胞会引起内皮细胞活化,促进白细胞停滞,导致视网膜通透性增强,而Gr1-/CCR2-/CX3CR1hi细胞会保护糖尿病患者的BRB。我们将研究控制这些亚型对DR进展的影响。靶向单核细胞亚型可能是DR预防和治疗的理想策略。CellMax吗?

项目成果

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Steven F Abcouwer其他文献

Steven F Abcouwer的其他文献

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{{ truncateString('Steven F Abcouwer', 18)}}的其他基金

Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease
mTORC1 在视网膜神经节细胞生理和疾病中的作用
  • 批准号:
    10458570
  • 财政年份:
    2020
  • 资助金额:
    $ 45.24万
  • 项目类别:
Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease
mTORC1 在视网膜神经节细胞生理和疾病中的作用
  • 批准号:
    10229613
  • 财政年份:
    2020
  • 资助金额:
    $ 45.24万
  • 项目类别:
Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease
mTORC1 在视网膜神经节细胞生理和疾病中的作用
  • 批准号:
    10673155
  • 财政年份:
    2020
  • 资助金额:
    $ 45.24万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    10222701
  • 财政年份:
    2018
  • 资助金额:
    $ 45.24万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    9761528
  • 财政年份:
    2018
  • 资助金额:
    $ 45.24万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    10459620
  • 财政年份:
    2018
  • 资助金额:
    $ 45.24万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    9979905
  • 财政年份:
    2018
  • 资助金额:
    $ 45.24万
  • 项目类别:
Bone Marrow Neuropathy Drives Diabetic Retinopathy
骨髓神经病变导致糖尿病视网膜病变
  • 批准号:
    8731390
  • 财政年份:
    2013
  • 资助金额:
    $ 45.24万
  • 项目类别:
Regulation of Retinal Cell Death in Diabetes
糖尿病视网膜细胞死亡的调节
  • 批准号:
    9124905
  • 财政年份:
    2010
  • 资助金额:
    $ 45.24万
  • 项目类别:
Regulation of Retinal Cell Death in Diabetes
糖尿病视网膜细胞死亡的调节
  • 批准号:
    8174942
  • 财政年份:
    2010
  • 资助金额:
    $ 45.24万
  • 项目类别:

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