期刊
LIFE SCIENCE ALLIANCE
卷 3, 期 3, 页码 -出版社
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.201900481
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资金
- National Institutes for Health (NIH) [DK107585]
- Clinical and Translational Science Award (CTSA) [UL1TR001442, AI141630, CA238042, CA100768, R00-CA151673]
- Padres Pedal the Cause/Rady Children's Hospital Translational PEDIATRIC Cancer Research Award
- DiaComp Pilot and Feasibility award (Augusta University)
- NIH/National Center for Advancing Translational Sciences [UG3TR002968, PTC 2017]
- Moores Cancer Center
- NIH training grant [DK 0070202]
- NIH CTSA-funded career-development award [1TL1TR001443]
- NIH Diversity Supplement award
- Chancellor's Research Excellence Scholarships for Graduate Students (UCSD)
The gut barrier separates trillions of microbes from the largest immune system in the body; when compromised, a leaky gut barrier fuels systemic inflammation, which hastens the progression of chronic diseases. Strategies to detect and repair the leaky gut barrier remain urgent and unmet needs. Recently, a stress-polarity signaling (SPS) pathway has been described in which the metabolic sensor, AMP-kinase acts via its effector, GIV (also known as Girdin) to augment epithelial polarity exclusively under energetic stress and suppresses tumor formation. Using murine and human colon-derived organoids, and enteroid-derived monolayers (EDMs) that are exposed to stressors, we reveal that the SPS-pathway is active in the intestinal epithelium and requires a catalytically active AMP-kinase. Its pharmacologic augmentation resists stress-induced collapse of the epithelium when challenged with microbes or microbial products. In addition, the SPS-pathway is suppressed in the aging gut, and its reactivation in enteroid-derived monolayers reverses aging-associated inflammation and loss of barrier function. It is also silenced during progression of colorectal cancers. These findings reveal the importance of the SPS-pathway in the gut and highlights its therapeutic potential for treating gut barrier dysfunction in aging, cancer, and dysbiosis.
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