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

基本信息

  • 批准号:
    10485363
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 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:
    2016-10-01 至 2026-09-30
  • 项目状态:
    未结题

项目摘要

Alcohol-associated diseases and disorders (AAD) account for over 5% of global health problems. AAD is more common among veterans, and more than 30% of young men in the military are heavy drinkers, twice as much as their civilian counterparts. Alcohol misuse is high in veterans exposed to combat-related traumatic stress or experiencing post-traumatic stress disorder (PTSD). AAD and PTSD symptoms feedback into one another and impede the recovery from both disorders. Therefore, treating AAD patients comorbid with PTSD is complicated and requires a deeper understanding of the cross-talk between alcohol and stress. Behavioral intervention is not efficacious in moderate to heavy alcohol drinkers, and its benefit in PTSD is inconsistent. The common conditions associated with AAD and PTSD are endotoxemia and systemic inflammation. Clinical and experimental evidence indicates that intestinal dysbiosis (depleted beneficial species, increased pathobionts, and decreased diversity) is necessary for developing endotoxemia and systemic inflammation. Therefore, dysbiosis is a crucial therapeutic target for treating AAD and PTSD. The critical barrier in this field is that the mechanisms involved in alcohol and stress-induced dysbiosis are poorly defined. There is no treatment with clear evidence of efficacy available for treating AAD or AAD comorbid with PTSD. Our long-term goal is to describe the pathophysiology of AAD-stress comorbidity and develop novel therapeutic strategies by targeting the gut microbiota. Our preliminary studies have identified that: 1) chronic restraint stress (CRS) and corticosterone exacerbate ethanol (EtOH)-induced gut barrier dysfunction, endotoxemia, systemic inflammation, liver damage, and neuroinflammation in mice. 2) Corticosterone reinforces EtOH-induced dysbiosis and depletion of Paneth cell a-defensin mRNA. 3) Deleting intestinal glucocorticoid receptor (GR) prevents corticosterone and EtOH-induced gut permeability and systemic response. 4) Knockout of intestinal NR3C1 (encoding GR) prevents corticosterone and EtOH-induced defensin mRNA depletion and dysbiosis. 5) Corticosterone and EtOH reduce intestinal mRNA for T-cell receptor 4 (TCF4), the transcription factor required for a-defensin production. These findings form the scientific premise and support the central hypothesis that the Paneth cell GR drives stress and alcohol-associated dysbiosis, gut permeability, and systemic responses by suppressing a-defensin production. Our overall objective is to define the role of Paneth cell GR and the downstream mechanism in stress and alcohol-associated organ damage and identify the therapeutic potential of a-defensins in treating AAD comorbid with chronic stress. This objective will be achieved by determining that 1) Paneth cell GR is required for stress and alcohol-induced TCF4 down- regulation, a-defensin depletion, and microbiota dysbiosis. 2) TCF4 down-regulation mediates GR's role in stress and alcohol-induced a-defensin depletion and dysbiosis. 3) GR-mediated TCF4 regulation in Paneth cells plays a role in stress and alcohol-induced gut permeability and systemic response. 4) GR-regulated microbiota composition reinforces alcohol-induced gut permeability and systemic response. 5) HD5 and HD6 attenuate stress and alcohol-induced intestinal dysbiosis and systemic response. 6) Stress and alcohol-induced dysbiosis and multi-organ injury is reversed by HD5 and HD6. The proposed research will utilize novel in vitro and in vivo models to identify GR, a-defensins, and dysbiosis as therapeutic targets for AAD and PTSD.
酒精相关疾病和失调占全球健康问题的5%以上。油气地质

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:
    --
  • 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:
    --
  • 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:
    10474225
  • 财政年份:
    2022
  • 资助金额:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 项目类别:
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