Modulation of mitochondrial respiration to treat colitis

调节线粒体呼吸来治疗结肠炎

基本信息

项目摘要

The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data that demonstrate it to be a predictor of remission. Unfortunately, many IBD patients remain refractory or lose responsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show that reduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC). Consistently, increased expression of mitochondrial respiratory chain genes has been shown to predict favorable Crohn’s disease (CD) outcomes. Based on these results and our own data, we hypothesize that a critical driver of chronic ulceration in IBD is the failure of intestinal epithelial cells (IEC) to increase mitochondrial respiration. In studies leading up to this submission we found that mitochondrial deficiency caused poor ulcer healing due to inadequate crypt fissioning occurring at ulcer edges (Progress Report). These findings led us to develop a novel gold (Au)- based drug based on the current safe and effective gold therapy for Rheumatoid arthritis (Auranofin). This new drug, AuPhos, localizes to mitochondria where it increases mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) production. Induction of low levels of “endogenous” mtROS are known to promote healthy adaptive responses in cells including anti-oxidant enzyme activities (Background). In preliminary studies, we found that oral AuPhos 1) enhances mucosal repair in DSS colitis, 2) increases IEC mitochondrial oxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS), 3) mtROS and H2O2 production in IEC as well as 4) phosphoinositides-3 kinase (PI3K) and nuclear factor erythroid 2-related factor (Nrf2) signaling with 5) improved expression of proteins that induce mitochondrial biogenesis [peroxisome proliferator activated receptor-γ coactivator 1 alpha (PGC1α) and transcription factor A, mitochondrial (TFAM). Studies proposed in Aim 1 interrogate mitochondrial function under baseline conditions to allow assessment of AuPhos-induced changes in mitochondrial mass, activity (mtROS) and OCR, ATP turnover, electron transport chain (ETC) activity, induction of adaptive responses [anti-oxidant catalase, MnSOD (superoxide dismutase) and glutathione (reduced/oxidized)] as well as assess changes in tissue oxidant stress (4HNE, protein carbonylation, nitrotyrosine IHC). Aim 2 will build upon these studies by evaluating AuPhos effects in TNF-stimulated small bowel (SB) and colonic organoids from veterans (normal and IBD). Studies in 3D organoids will allow for mechanistic testing of AuPhos-induced crypt budding and IEC gene expression. Results of Aim 2 will instruct studies in Aim 3A that study therapeutic effects of AuPhos on IEC gene expression and crypt fissioning that heal ulcers in DSS colitis. In Aim 3B, scRNAseq analysis of human biopsies incubated with AuPhos will allow us to examine induction of mitochondrial gene expression in discrete IEC clusters. Proposed studies are driven by a novel hypothesis that restoration of IEC mitochondrial respiration is a key step in mucosal healing. Together, these “preclinical” studies with a VA-sponsored new drug (AuPhos) have the potential of transitioning this agent to the therapy of IBD in veterans.
粘膜愈合在炎症性肠病(IBD)中的重要性来源于临床数据

项目成果

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Terrence A. Barrett其他文献

T cell-induced diarrhea mediated by tumor necrosis factor (TNF) and downregulation of Na+/K+ ATPase
  • DOI:
    10.1016/s0016-5085(00)85375-5
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Daniel Marnah;Arshad A. Gazi;Mark W. Musch;Eugene B. Chang;Terrence A. Barrett
  • 通讯作者:
    Terrence A. Barrett
Prevalência elevada dos sintomas de refluxo gastro-esofágico em doentes com DPOC
DPOC 胃食管反流病的流行病
  • DOI:
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Babak Mokhlesi;A. Morris;C.;A. Curcio;Terrence A. Barrett;David W. Kamp
  • 通讯作者:
    David W. Kamp
Oral Administration of Avian Tumor Necrosis Factor Antibodies Effectively Treats Experimental Colitis in Rats
  • DOI:
    10.1023/a:1005554900286
  • 发表时间:
    2000-12-01
  • 期刊:
  • 影响因子:
    2.500
  • 作者:
    Katherine L. Worledge;Ronald Godiska;Terrence A. Barrett;John A. Kink
  • 通讯作者:
    John A. Kink
Mitochondrial function and gastrointestinal diseases
线粒体功能与胃肠道疾病
  • DOI:
    10.1038/s41575-024-00931-2
  • 发表时间:
    2024-05-13
  • 期刊:
  • 影响因子:
    51.000
  • 作者:
    Parsa S. Haque;Neeraj Kapur;Terrence A. Barrett;Arianne L. Theiss
  • 通讯作者:
    Arianne L. Theiss
Mo1955 Oxidative DNA Damage and Double-Strand Breaks Drive Colitis-Associated Cancer in IL 10-/- Mice
  • DOI:
    10.1016/s0016-5085(13)62607-4
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Adrian Frick;Vineeta Khare;Michaela Lang;Gregor Paul;Terrence A. Barrett;Christoph Gasche
  • 通讯作者:
    Christoph Gasche

Terrence A. Barrett的其他文献

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{{ truncateString('Terrence A. Barrett', 18)}}的其他基金

The Role of Crypt Fissioning in IBD Ulcer Healing
隐窝分裂在 IBD 溃疡愈合中的作用
  • 批准号:
    10609794
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The Role of Crypt Fissioning in IBD Ulcer Healing
隐窝分裂在 IBD 溃疡愈合中的作用
  • 批准号:
    10358590
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Peripheral Blood Exosome Lipids as Biomarkers of Disease Activity in Crohn’s Disease
外周血外泌体脂质作为克罗恩病疾病活动的生物标志物
  • 批准号:
    9767782
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Modulation of mitochondrial respiration to treat colitis
调节线粒体呼吸来治疗结肠炎
  • 批准号:
    10367171
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
The role of Axin2+ stem cells in ulcer healing during colitis.
Axin2 干细胞在结肠炎溃疡愈合中的作用。
  • 批准号:
    9138122
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Regulation of Intestinal Stem Cell Activation in Colitis
结肠炎中肠道干细胞激活的调节
  • 批准号:
    8893972
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Regulation of Intestinal Stem Cell Activation in Colitis
结肠炎中肠道干细胞激活的调节
  • 批准号:
    8693314
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Regulation of Intestinal Stem Cell Activation in Colitis
结肠炎中肠道干细胞激活的调节
  • 批准号:
    8441348
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Lymphoepithelial interactions in IBD
IBD 中的淋巴上皮相互作用
  • 批准号:
    7173828
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
Lymphoepithelial interactions in IBD
IBD 中的淋巴上皮相互作用
  • 批准号:
    7388886
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:

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3-硝基酪氨酸在骨骼肌和心脏老化中的作用
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  • 批准号:
    11670636
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