Sirtuins and nuclear receptors in aging and age-associated diseases

National Institute Of Environmental Health Sciences

Investigators

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Abstract

In the past year, our efforts focus on the role of SIRT1 and/or protein acylation in regulation of embryonic stem cell metabolism, differentiation, and animal development, and the impact of intestinal epithelial glucocorticoid signaling on intestinal inflammation, anti-tumor immunity, and tumorigenesis. Synthetic immunosuppressive glucocorticoids are widely used to control inflammatory bowel disease (IBD). However, the impact of this stress signaling on intestinal tumorigenesis remains controversial. In collaboration with Dr. John Cidlowski's group at the NIEHS and Dr. Shuang Tang's group at Fudan University Cancer Center, we recently report that intestinal epithelial glucocorticoid receptor (GR) signaling promotes chronic intestinal inflammation associated colorectal cancer in both humans and mice. In colorectal cancer patients, GR is enriched in intestinal epithelial cells and high epithelial GR is associated with poor prognosis. In mice, intestinal epithelium-specific deletion of GR (GR iKO) increases macrophage infiltration, improves tissue recovery, and enhances antitumor response, and suppresses tumor formation in a chronic inflammation-associated colorectal cancer model. Furthermore, oral GC administration in the early phase of tissue injury delays recovery and accelerates the formation of aggressive colorectal cancers. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that although synthetic glucocorticoid treatment for IBD should be used with caution in colorectal cancer patients, there is a therapeutic window for glucocorticoid therapy during colorectal cancer development. A paper describing this study was published in Elife (Tang et al., JCI Insight, 2021). Cardiomyocytes, cells responsible for generating contractile force in the heart, require elongation and alignment during maturation around birth (perinatal stage). this morphological remodeling is crucial for formation of the highly organized intra- and inter-cellular structures for spatially and temporally ordered contraction in adult cardiomyocytes. However, control of cardiomyocyte alignment remains elusive. Here we report that SIRT1, the most conserved NAD+-dependent protein deacetylase highly expressed in perinatal heart, plays an important role in regulating cardiomyocyte remodeling during development. SIRT1 deficiency impairs alignment of cardiomyocyte and disrupts normal beating patterns at late developmental stages in an in vitro differentiation system from human embryonic stem cells. Consistently, deletion of SIRT1 at a late developmental stage in mouse embryos induces the irregular distribution of cardiomyocytes and misalignment of myofibrils, and reduces the heart size. At the molecular level, we found that the expression of several genes involved in cell movement in response to chemical stimulus is dramatically blunted during maturation of SIRT1 deficient cardiomyocytes. Pharmacological inhibition of these signaling suppresses cardiomyocyte alignment. Our study identifies a regulatory factor that modulates cardiomyocyte alignment at the inter-cellular level during maturation. A paper describing this study was published in Journal of Cell Science (Fang et al., Journal of Cell Science, 2022). In response to COVID-19 pandemic, we initiated two projects to test whether targeting NAD metabolism or inositol phosphate metabolism could regulate anti-viral immunity of immune cells or viral replication in human cells. The inositol phosphate is in collaboration with Dr. Stephen Shears at the NIEHS. Both projects are still ongoing. This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.