Radiation-Induced Paneth Cell Dysfunction

辐射引起的潘氏细胞功能障碍

基本信息

项目摘要

Public exposure to radiation due to large-scale radiation incidents is a rising global concern. Acute radiation syndrome (ARS) is associated with high morbidity and mortality, but no FDA-approved therapeutics for gastrointestinal (GI) ARS. Therefore, delineating the mechanisms underlying radiation injury to develop targeted medical countermeasures (MCM) is a high priority. The GI mucosal immune system is susceptible to ionizing radiation, and dysfunctional mucosal immunity is a major contributing factor in the pathogenesis of ARS. The gap in this field is that the precise mechanisms by which radiation impairs the mucosal immune system and immune dysfunction-mediated dysbiosis of gut microbiota and multi-organ injury (MOI) are poorly defined. The long-term goal of our research is to identify the radiation- sensitive immune-specific pathways and test and develop novel immune dysfunction-targeted MCM for radiation exposure. Endotoxemia and systemic inflammation are common conditions associated with morbidity and mortality in ARS. Clinical and experimental evidence indicates that intestinal dysbiosis (depleted beneficial species, increased pathobionts, and decreased diversity) is a prerequisite for developing endotoxemia, systemic inflammation, and MOI. a-Defensins are antibacterial peptides secreted from Paneth cells, the highly specialized intestinal epithelial cells, to maintain microbiota homeostasis. Human Paneth cells produce two a-defensins - defensin 5 (HD5) and 6 (HD6). Our preliminary data show that ionizing radiation in mouse intestine 1) depletes Paneth cell a-defensins, 2) reduces mucosal Tcf4 mRNA, 3) alters microbiota composition, 4) disrupts epithelial barrier, and 5) consequent mucosal inflammatory response, endotoxemia, and systemic inflammation. Importantly, HD5 administered in the diet at 24 h post-irradiation mitigates altered gut microbiota, gut barrier dysfunction, and endotoxemia. These findings form the scientific premise (FIG 1) and support the central hypothesis that “HD5 mitigates GI-ARS by reversing dysbiosis of gut microbiota and epithelial barrier dysfunction, leading to mitigation of endotoxemia and systemic inflammation.” We will test this hypothesis by determining that 1) Ionizing radiation downregulates Wnt signaling in intestinal Paneth cells, 2) TCF4 down-regulation mediates radiation-induced a-defensin depletion and consequent dysbiosis, 3) a-Defensin supplementation reverses radiation-induced dysbiosis of gut microbiota, 4) Radiation-induced dysbiosis drives gut barrier dysfunction, endotoxemia, and systemic inflammation, 5) the lowest and most effective dose of HD5 in mitigating GI- ARS, 6) the ideal time window for post-exposure (+24-96 h) effectiveness of HD5 to reverse GI-ARS, and 7) the HD5 treatment paradigm to increase the survival rates from lethal dose radiation. .
由于大规模辐射事件造成的公众辐射暴露是一个日益引起全球关注的问题。急性

项目成果

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RADHAKRISHNA RAO其他文献

RADHAKRISHNA RAO的其他文献

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{{ truncateString('RADHAKRISHNA RAO', 18)}}的其他基金

Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage.
定义肠道钙通道在酒精性肝损伤中的作用。
  • 批准号:
    10390126
  • 财政年份:
    2022
  • 资助金额:
    $ 49.16万
  • 项目类别:
Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage.
定义肠道钙通道在酒精性肝损伤中的作用。
  • 批准号:
    10590757
  • 财政年份:
    2022
  • 资助金额:
    $ 49.16万
  • 项目类别:
Mitigation of GI-ARS by Lactobacillus species
乳酸菌物种缓解 GI-ARS
  • 批准号:
    10570082
  • 财政年份:
    2022
  • 资助金额:
    $ 49.16万
  • 项目类别:
Radiation-Induced Paneth Cell Dysfunction
辐射引起的潘氏细胞功能障碍
  • 批准号:
    10686031
  • 财政年份:
    2022
  • 资助金额:
    $ 49.16万
  • 项目类别:
Impact of Stress on Alcoholic Gut Injury
压力对酒精性肠道损伤的影响
  • 批准号:
    9143185
  • 财政年份:
    2016
  • 资助金额:
    $ 49.16万
  • 项目类别:
Impact of Stress on Alcohol-Associated Gut Injury and Systemic Response
压力对酒精相关肠道损伤和全身反应的影响
  • 批准号:
    10485363
  • 财政年份:
    2016
  • 资助金额:
    $ 49.16万
  • 项目类别:
Intestinal Mucosal Protection by Epidermal Growth Factor
表皮生长因子对肠粘膜的保护
  • 批准号:
    8994319
  • 财政年份:
    2015
  • 资助金额:
    $ 49.16万
  • 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
  • 批准号:
    8362842
  • 财政年份:
    2011
  • 资助金额:
    $ 49.16万
  • 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
  • 批准号:
    8170447
  • 财政年份:
    2010
  • 资助金额:
    $ 49.16万
  • 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
  • 批准号:
    7954982
  • 财政年份:
    2009
  • 资助金额:
    $ 49.16万
  • 项目类别:

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