Brain-gut-retina axis in diabetic retinopathy

糖尿病视网膜病变中的脑-肠-视网膜轴

基本信息

  • 批准号:
    10595142
  • 负责人:
  • 金额:
    $ 55.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Summary Abstract This application puts for the notion of a brain-gut- retinal axis that becomes dysfunctional in diabetic retinopathy (DR). The innate immune system has been strongly implicated in the pathogenesis of DR, but less is known about the role of the adaptive immune system. At the interface of these two systems is a critical population of cells, Th17 cells, that typically reside in the gut during health. Th17 cells have homeostatic properties, mediating host defense against bacterial and fungal infections; however, it remains unclear how intestinal Th17 cells integrate diverse signals into a set of cellular programs that allow them to maintain tissue homeostasis yet also become pathogenic, serving as primary drivers of tissue inflammation. We have identified a critical role of somatostatinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) in regulation of immune function through “loss of function” studies and “gain of function studies. SST expression is dramatically reduced in the PVN of diabetic animals. Hypothalamic dysfunction, as seen in diabetes, has the capacity to induce injury directly through hyperactivation of sympathetic nerves. Based on preliminary and published data, we put for the hypothesis that: Diabetes-induced loss of inhibitory SST neurons in the PVN drives increased autonomic input to the intestine shifting Th17 cells from a homeostatic to a pathologic state. Pathologic Th17 cells leave the intestine and traffic to areas of tissue injury such as the retina in DR. In the retina the pathologic Th17 cells secrete proinflammatory cytokines that recruitment innate immune cells into the retina exacerbating DR. To examine this hypothesis, we propose the following aims: Aim 1: To test if impaired function of hypothalamic SST neurons in diabetes contributes to hyperactivity of autonomic efferents to the gut and increases activation of enteric neurons. Aim 2: To selectively ablate SST PVN neurons (in the absence of diabetes) and evaluate if this results in increased autonomic input to the gut and a shift from “homeostatic” Th17 cells to a “pathogenic” Th17 cells that migrate to the retina and recruit circulating immune cells. Aim 3: To determine if maintaining hypothalamic SST levels at nondiabetic levels in diabetic mice will preserve the function of homeostatic Th17 cells in the gut and prevent their recruitment to the retina delaying the development of DR. Impact: SST analogues may provide an important complementary strategy for DR management by preventing increased sympathetic drive to the gut and Th17 cell dysfunction.
总结抽象

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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CHARLES J FRAZIER其他文献

CHARLES J FRAZIER的其他文献

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{{ truncateString('CHARLES J FRAZIER', 18)}}的其他基金

Novel Aspects of Central Oxytocin Signaling Relevant to Mood/Anxiety Disorders
与情绪/焦虑障碍相关的中枢催产素信号的新方面
  • 批准号:
    9014566
  • 财政年份:
    2015
  • 资助金额:
    $ 55.06万
  • 项目类别:
Novel Aspects of Central Oxytocin Signaling Relevant to Mood/Anxiety Disorders
与情绪/焦虑障碍相关的中枢催产素信号的新方面
  • 批准号:
    8888289
  • 财政年份:
    2015
  • 资助金额:
    $ 55.06万
  • 项目类别:
CB1R independent effects of cannabinoids on synaptic physiology in the CNS.
大麻素对中枢神经系统突触生理学的 CB1R 独立影响。
  • 批准号:
    8225252
  • 财政年份:
    2011
  • 资助金额:
    $ 55.06万
  • 项目类别:
CB1R independent effects of cannabinoids on synaptic physiology in the CNS.
大麻素对中枢神经系统突触生理学的 CB1R 独立影响。
  • 批准号:
    8048639
  • 财政年份:
    2011
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus.
齿状回中的内源性大麻素和补品 GABA。
  • 批准号:
    7093652
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
  • 批准号:
    7656750
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
  • 批准号:
    7460588
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus.
齿状回中的内源性大麻素和补品 GABA。
  • 批准号:
    7473458
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
  • 批准号:
    7242587
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
  • 批准号:
    6903677
  • 财政年份:
    2005
  • 资助金额:
    $ 55.06万
  • 项目类别:

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