Research

Dr. Chapkin is an expert in dietary/microbial modulators related to prevention of cancer and chronic inflammatory diseases.  He has been continuously funded by NIH for the past 27 years and is an NCI R35 Outstanding Investigator (2016-2023).  This very prestigious award is given to an exceptional and long-established cancer researcher who has been continuously funded by the NIH.  The award will fund Dr. Chapkin’s cancer research program for the next 7 years.  Dr. Chapkin has made highly significant contributions in cancer chemoprevention and inflammation biology with specific emphasis in: (i) elucidation of signal transduction processes in intestinal stem cells, (ii) membrane biology and nutritional modulation of organ membrane structure and function, (iii) investigation of the role of inflammation as a critical factor in cancer development, and its modulation by environmental/botanical agents, (iv) establishment of models for chronic inflammation and cancer prevention studies, and (v) development of novel noninvasive Systems Biology-based methodologies to assess crosstalk between the gut microbiome and the host transcriptome and its application to translational research. These activities, together with a history of basic and translational (biomarkers) research using cutting-edge genomics and computational biology methodologies, demonstrate that Dr. Chapkin has the scientific credentials necessary to generate seminal discoveries linking microbiota and host responses to chronic diseases.

Contribution to Science

Our central goal is to (1) understand dietary chemoprevention at a fundamental level, and (2) to test pharmaceutical agents in combination with dietary (countermeasures to the Western diet) to more effectively improve gut health and reduce systemic chronic inflammation.  Since diet influences gut microbiota composition and metabolite production, to unravel the interrelationships among gut health and the structure of the gut microbial ecosystem, we are in the process of evaluating (using preclinical models and humans) how the gut microbiome modulates intestinal cells, innate immune cells and tumors.  As part of this endeavor, we are modeling, at the molecular level, the dynamic relationship between diet and gut microbe-derived metabolites which modulate chronic inflammation and the hierarchical cellular organization of the intestine, e.g., stem cell niche.  Work in the lab related to intestinal “phenotypic flexibility” falls into four specific areas:

 

  1. Development of a novel noninvasive methodology to monitor HOST/MICROBE INTERACTION.

Early detection can be considered a method for prevention in the sense that it can prevent serious morbidity and mortality.  To address this need, our team has identified novel early detection biomarkers, e.g., genomic signals, to classify/predict chronic inflammation, metabolic profiling, immune status, and gut barrier function on a molecular level in mouse models and humans.  For this purpose, we mathematically model dynamical system behavior for the purpose of deriving therapeutic strategies to alter undesirable cellular behavior.  Outcomes include the prediction of new nutraceutical / drug targets based on intracellular signaling pathways.  Cutting edge applications include: (i) the influences of diet and the gut microbiome on host (using exfoliated cells) epigenetic modulation in neonates, and (ii) simultaneous analysis of the multivariate structure between the gut metatranscriptome and host transcriptome using noninvasive methodologies.

M. Wang, M. Li, C.B. Lebrilla, R.S. Chapkin, I. Ivanov and S.M. Donovan. Fecal microbiota composition of breast-fed infants differs from formula-fed and is correlated with human milk oligosaccharides consumed. Journal of Pediatric Gastroentrology & Nutrition 60:825-833, 2015.  PMID:25651488 PMCID: PMC4441539

J.M. Knight, L.A. Davidson, D. Herman, C.R. Martin, J.S. Goldsby, I.V. Ivanov, S.M. Donovan and R.S. Chapkin.  Non-invasive analysis of intestinal development in premature and full term infants using RNA-Sequencing.  Scientific Reports Nature 4:5453; DOI:10.1038/srep05453, 2014.  PMCID:PMC4071321

S. Schwartz, I. Friedberg, I.V. Ivanov, L.A. Davidson, J.S. Goldsby, D.B. Dahl, D. Herman, M. Wang, S.M. Donovan and R.S. Chapkin. A Metagenomic study of diet-dependent interaction between gut microflora and host in infants reveals differences in developmental and immune responses. Genome Biology 13:R32 doi:10.1186/gb-2012-13-4-r32, 2012. PMCID:PMC3446306

R.S. Chapkin, C. Zhao, I. Ivanov, L.A. Davidson, J.S. Goldsby, J.R. Lupton, R.A. Mathai, M. Siegel, D. Rai, M. Russell, S.M. Donovan and E.R. Dougherty.  Non-invasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells.  American Journal of Physiology 298:G582-G589, 2010.  PMID: 20203060  PMCID: PMC2867429

 

  1. Effects of dietary lipidS on membrane structure and function.

Select long chain polyunsaturated fatty acids, e.g., arachidonic acid (AA), regulate inflammation and promote cancer development.  Previous studies have targeted prostaglandin enzymes in an attempt to modulate AA metabolism.  We determined the utility of antagonizing tissue AA levels as a novel approach to suppressing AA-derived eicosanoids.  Specifically, we globally disrupted the Fads1 (∆5 desaturase) gene in mouse tissues.  This resulted in a profound increase in one- and a concurrent decrease in two-series-derived prostaglandins.   The lack of AA-derived eicosanoids, e.g., PGE2, was associated with perturbed intestinal crypt proliferation, immune cell homeostasis, and a heightened sensitivity to acute inflammatory challenge.  In addition, Null mice failed to thrive, dying off by 12 weeks of age.  Dietary supplementation with AA extended the longevity of Null mice to levels comparable to Wild type mice.  We propose that this new mouse model will expand our understanding of how long chain PUFA and their metabolites mediate inflammation and modulate diseases such as NAFLD.

 

H.F. Turk, J.M. Monk, Y.Y. Fan, E.S. Callaway, B. Weeks and R.S. Chapkin.  Inhibitory effects of omega-3 fatty acids on injury induced epidermal growth factor transactivation contribute to delayed wound healing.  American Journal of Physiology 304:C905-C917, 2013.  PMID:23426968.

Y.Y. Fan, J. Monk, T. Hou, E. Callaway, L. Vincent, B. Weeks, P. Yang and R.S. Chapkin.  Characterization of an arachidonic acid-deficient (FADS1 knock-out) mouse model.  Journal of Lipid Research 53:1287-1295, 2012.  PMCID: PMC3371240

H.F. Turk, R. Barhoumi, R.S. Chapkin.  Alteration of EGFR spatiotemporal dynamics suppresses signal transduction. PLoS One 7(6):e39682, June, 2012. doi:10.1371/journal.pone.0039682 PMCID: PMC3384615

R.S. Chapkin, N. Wang, Y.Y. Fan, J.R. Lupton and I.A. Prior.  Docosahexaenoic acid alters the size and distribution of cell surface microdomains.  Biochimica et Biophysica Acta – Biomembranes 1778:466-471, 2008. PMCID:PMC2244794

 

  1. Investigation of the role of DietarY and microbial Ligands as MODIFIERS of inflammation aND colon cancer development.

Projects in this research area are designed to assess how microbiota-derived tryptophan metabolites mediate AhR-dependent intestinal function. Since transformation of adult stem cells is an extremely important route towards initiating intestinal cancer, we have interrogated the effect of diet and microbiota-derived AhR ligands on intestinal stem cell homeostasis and colon tumorigenesis using tissue and stem cell-specific AhR knock out and control compound mice.  This objective is supported by our novel preliminary data indicating that microbial-derived AhR ligands have a direct effect on the intestinal epithelium (without the contribution of the mesenchymal niche) and modulate stemness.  In addition, we have demonstrated that microbiota-derived AhR ligand levels are decreased under high fat diet (obesogenic) conditions.  This is noteworthy, because a growing body of preclinical and epidemiological data indicate that the risk of colon cancer is strongly associated with obesity.  Collectively, our results provide a critical new paradigm in understanding the molecular mechanisms through which microbes modulate colon cancer risk. 

Y. Cheng, U.H. Jin, C.D. Allred, A. Jayraman, R.S. Chapkin and S. Safe. Aryl hydrocarbon receptor activity of tryptophan metabolites in Young Adult Mouse Colonocytes. Drug Metabolism & Disposition 43:1536-1543, 2015.  PMID: 25873348

Y.Y. Fan, L.A. Davidson, E.S. Callaway, G.A. Wright, S. Safe and R.S. Chapkin.  A bioassay to measure energy metabolism in mouse colonic crypts, organoids and sorted stem cells.   American Journal of Physiology-GI 309:G1-9, 2015. PMID: 25977509

U.H. Jin, S.O. Lee, G. Sridharan, K. Lee, L.A. Davidson, A. Jayaraman, R.S. Chapkin, R. Alaniz and S. Safe.  Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities.  Molecular Pharmacology 85:777-788, 2014. PMID:24563545.

V. DeClercq, D.N. McMurray and R.S. Chapkin. Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Letters 369:336-343, 2015.  PMID:26455770

 

  1. Synergistic effectS of SYSTEMIC AND LUMENAL METABOLITES ON INTESTINAL STEM CELLS AND DIFFERENTIATED COLONOCYTES.

Projects in this research area are designed to assess how the chemoprotective properties of dietary lipid are altered when a highly fermentable fiber, pectin, rather than a poorly fermentable fiber, cellulose, is added to the diet. This protective effect is mediated in part by the up-regulation of targeted apoptosis of DNA adducts during tumor initiation. Our findings indicate that highly fermentable fiber, which generates butyrate in the colon, only has chemotherapeutic value when n-3 PUFA is the lipid source.   With respect to a molecular mechanism of action, n-3 PUFA and butyrate (a microbial fermentation product), in combination, synergistically induce a novel p53-independent, oxidation-sensitive, mitochondrial Ca2+-dependent (intrinsic) pathway.  This critical observation emphasizes the need to examine both the lipid and fiber composition of diets.  The lab is now focusing on the impact of gut-related metabolites on intestinal stem cell biology in vivo and ex vivo using a colonic organoid model system.

 

L.A. Davidson, E. Callaway, E. Kim, B. Weeks, Y.Y. Fan, C.D. Allred and R.S. Chapkin.  Targeted deletion of p53 in Lgr5-expressing intestinal stem cells promotes colon tumorigenesis in a preclinical model of colitis-associated cancer.  Cancer Research 75:5392-5397, 2015. PMID:26631266.

E.J. Kim, L.A. Davidson, R.S. Zoh, B.S. Patil, G.K. Jayaprakasha, E.S. Callaway, C.D. Allred, N.D. Turner and R.S. Chapkin.  Homeostatic responses of colonic LGR5 stem cells following acute in vivo exposure to a genotoxic carcinogen.  Carcinogenesis (In Press).  PMID:26717997.

Y.Y. Fan, L.A. Davidson, E.S. Callaway, J.S. Goldsby and R.S. Chapkin.  Differential effects of 2 and 3-series prostaglandins on in vitro expansion of Lgr5+ intestinal stem cells.  Carcinogenesis 35:606-612, 2014. PMID:24336194

L.A. Davidson, J.S. Goldsby, E.S. Callaway, N. Barker and R.S. Chapkin.  Alteration of colonic stem cell signatures during the regenerative response to injury.  Biochmicia et Biophysica Acta-Molecular Basis of Disease 1822:1600-1607, 2012. PMID: 22750333

 

Complete List of Published Work in MyBibliography:  From a total of 245 PUBLICATIONS:

http://www.ncbi.nlm.nih.gov/sites/myncbi/robert.chapkin.1/bibliography/41155665/public/?sort=date&direction=ascending