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Principal Investigator: Xiaoling Li
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2022
Award: $3,474,264
Funding agency: National Institute of Environmental Health Sciences
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Acylation><Adult><Adult Human><Age><Aging><Animals><Antitumor Response><Basal Transcription Factor><Basal transcription factor genes><Birth><Body Tissues><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cancer Center><Cancer Model><Cancer Prognosis><CancerModel><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Communication and Signaling><Cell Components><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Process><Cell Signaling><Cell Structure><Cell physiology><Cells><Cellular Function><Cellular Metabolic Process><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cellular Structures><Chemicals><Chronic><CoV emergence><CoV-2><CoV2><Collaborations><Colo-rectal Cancer><Colon or Rectum><Colorectal><Colorectal Cancer><Cues><Deacetylation><Development><Disease><Disorder><Dysfunction><ES cell><Embryo><Embryonic><Energy Expenditure><Energy Metabolism><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial><Epithelial Cells><Family><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genome Stability><Genomic Stability><Glucocorticoid Receptor><Glucocorticoids><Goals><HCoV><Heart><Heart Muscle Cells><Heart myocyte><Histones><Human><Immune><Immunes><Impairment><In Vitro><Infiltration><Inflammation><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inositol Phosphate Metabolism><Inositol Phosphate Metabolism Pathway><Inositol Phosphates><Intermediary Metabolism><Intracellular Communication and Signaling><Journals><L-Lysine><Link><Lipids><Lysine><Magazine><Mediating><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Modification><Molecular><Monitor><Morphology><Motility><Murine><Mus><Myofibrils><Mφ><NAD-Dependent Protein Deacetylases><NIEHS><National Institute of Environmental Health Sciences><Nuclear Receptors><Nutritional><Oncogenesis><Oral><Paper><Parturition><Pathogenesis><Pattern><Perinatal><Peripartum><Pharmacology><Phase><Physiology><Physiopathology><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Prognosis><Protein Acetylation><Protein Modification><Proteins><Publishing><RNA Expression><Receptor Signaling><Recovery><Regulation><Reporting><Research><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIRT1><SIRT1 gene><Science><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Deacetylases><Sir2-like Proteins><Sirtuin 1><Sirtuins><Stimulus><Stress><Subcellular Process><System><Testing><Therapeutic><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Tumor Immunity><Universities><Virus Replication><Wuhan coronavirus><acyl group><adulthood><ages><anti-tumor immunity><anti-tumor response><anti-viral immunity><antitumor immunity><antiviral immunity><biological signal transduction><bowel inflammation><cancer immunity><cardiac dimension><cardiac size><cardiomyocyte><cell metabolism><cell motility><cellular metabaolism><colo-rectal><colo-rectal cancer patients><colo-rectal cancer risk><colon cancer patients><colorectal cancer patients><colorectal cancer risk><colorectum><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><deacylation><developmental><embryonic stem cell><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><gut inflammation><hCoV19><hESC><heart dimension><heart dimension/size><heart size><human CoV><human ES cell><human ESC><human corona virus><human coronavirus><human embryonic stem cell><improved><inflamed bowel><inflamed gut><inflamed intestine><inflammatory disease of the intestine><inflammatory disorder of the intestine><injury to tissue><insight><intestinal autoinflammation><intestinal epithelium><intestinal inflammation><intestinal tumorigenesis><macrophage><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><nutritious><pathophysiology><predictive biomarkers><predictive marker><predictive molecular biomarker><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome-CoV><social role><stem cell of embryonic origin><tissue injury><transcription factor><tumor><tumorigenesis><viral multiplication><viral replication><virus multiplication>