Turner Research Lab

Dr. David P. TurnerAdvanced glycation end products (AGEs) are reactive metabolites produced when sugars come into contact with proteins and DNA. Pathogenic effects of AGEs include genetic infidelity, protein dysfunction and aberrant stress response.

David P. Turner, Ph.D.

Associate Professor,
Director of shRNA Technology
Director of AGE Analysis Resource
Department of Pathology & Laboratory Medicine
James Clyburn Research Center (BEB407)
843-876-2309
turnerda@musc.edu

Check out my TEDx talk

Research Goals

  1. To contribute to a greater understanding of the molecular consequences of the modern lifestyle on chronic diseases with a view to benefiting patients by increasing quality of life as well as life expectancy;
  2. Help train and develop the next generation of scientists;
  3. To promote community outreach efforts to inform and educate on the lab’s discoveries.

Current Lab Members

Lourdes Nogueira (Technician)
Bradley Krisanits (PhD Student)
Courtney Lloyd (Masters Student)

Research Program

Research Focus

The increasing occurrence of chronic conditions is a growing clinical and public health concern with distinct racial disparity. Our objective is to establish a direct cause and effect relationship between advanced glycation end products (AGEs), health disparity and chronic conditions. AGEs are reactive metabolites formed by glyoxidative, oxidative and lipoxidative stresses. The consumption of AGEs present in the modern diet is associated with the pathogenesis of adiposity, diabetes, neurodegenerative disorders, cancer and cardiometabolic comorbidities. Through their intrinsic ability to perpetuate immune mediated inflammatory stress AGEs found in the diet represent an early life exposure that may influence the onset and/or severity of multiple chronic conditions. AGEs promote inflammatory phenotypes by functioning as ligand for the receptor for AGE (RAGE) resulting in the activation of key transcriptional regulators (e.g. NFkB, STAT3, HIF1) and the aberrant release of pro-inflammatory paracrine factors (e.g. IL6, TNFalpha). RAGE mediated paracrine release results in lymphoid and myeloid cell recruitment which play a pathophysiological role in aberrant stress response which may contribute to multiple chronic conditions.

Useful Information Links:

1) The Mechanistic Implications of Dietary-AGE Consumption on Tumor Growth

The literature to date has shown only moderate promise for a role for AGEs on tumor biology. This is reflected by increases in cell growth, migration and invasion in vitro which were not supported by increased tumor growth in vivo. A caveat to these studies was that they are centered upon a single AGE peptide, usually derived from BSA, whey protein or collagen, followed by a subsequent assessment of their molecular effects on tumor epithelial cells. Using novel in vitro, ex vivo and in vivo experimental models we recapitulated a cellular microenvironment comprising of a wide spectrum of AGEs consisting of low and high molecular weight glycated peptides, lipids and nucleotides. This strategy has successfully demonstrated for the first time that AGEs derived from the diet can promote tumor growth and progression. This was confirmed in two independent breast and prostate cancer mouse models and was supported by ex vivo and in vitro cell studies. A high impact finding from our research is that AGEs in our diet accelerate prostate and breast tumor growth in vivo by functioning as ligand to the transmembrane receptor for AGE (RAGE). While RAGE expression is increased in tumor cells and is associated with aggressive tumors, our studies demonstrate that dietary-AGEs promote neoplastic growth by functioning as ligand to RAGE expressed in the tumor stroma not the tumor epithelial cells. Dietary-AGE activation of stromal RAGE caused a regulatory program of ‘activated stroma’ in the tumor microenvironment.

2) The Molecular Links Between Early Life Exposure to AGEs & Increased Breast Cancer Risk

Early-life exposures during mammary gland development influence the breast microenvironment to increase breast cancer risk. Mammary development during puberty is characterized by extensive tissue remodeling driven by developmentally regulated programs that engage both the mammary epithelium and the stromal matrix. Our studies show that dietary-AGE exposure can cause a regulatory program of ‘activated’ stroma in the mouse pubertal mammary gland. This was defined by receptor for AGE (RAGE) dependent increases in stromal recruitment to hyperproliferative terminal end buds (TEBs), and atypical hyperplasia formation in the forming mammary ducts. Critically, these dietary-AGE induced lesions persisted in adult mice and were not reversed by dietary intervention. Primary fibroblasts isolated from AGE fed wild type mice conferred tumor promoting abilities on both normal and tumor epithelial in ex vivo cultures, and ingestion of dietary-AGE in syngeneic mouse models accelerated breast tumor growth. Through the perpetual activation of a reactive stroma, dietary AGEs may represent an early life exposure which influences pubertal mammary gland development and future risk of breast cancer.

3) AGEing & RAGEing: Interventional Targets to Prevent Multimorbidity

As detailed above A high impact finding from our research is that AGE consumption by mice produces a common stromal activation signature in contrasting pathological conditions. The AGE mediated stromal signature was associated with both aberrant developmental programs during puberty and tumor growth and aggression in cancer models. In both cases the signature was characterized by:

  1. Increased levels of AGE and inflammatory markers in the circulation.
  2. Increased expression of molecular markers of fibroblast activation.
  3. Upregulation of RAGE, NFkB and c-MYC protein in fibroblasts and macrophages.
  4. Differential cytokine secretion.
  5. The differentiation of macrophages towards an inflammatory M1 phenotype.
  6. Increased cytotoxic T-cell proliferation.

Critically, all AGE mediated effects were dependent upon the expression of the transmembrane receptor for AGE (RAGE or AGER) in the stromal compartment. Inflammatory and oxidative stressors are essential elements for the onset and progression of chronic conditions. We hypothesize that “by acting as ligand for RAGE, AGE accumulation results in the cyclic activation of immune and oxidative stress in the stroma which creates a perpetual inflammatory microenvironment susceptible to the onset and progression of MCCs”.

4) AGEs & Diet: Their Impact on Animal Companion Well-Being & Lifespan

Most diets consumed by companion animals are highly processed. Such processed food is believed by many to have serious detrimental effects on animal well-being and even shorten their time with us. Research is urgently needed to define the relationship between modern pet foods and its ability to promote disease onset and accelerate the aging process in our animal companions. Animal food processing promotes a non-enzymatic reaction between proteins and sugars called the Maillard reaction which leads to the formation of reactive metabolites known as advanced glycation end products (AGEs). To improve taste, smell, and the color of many processed animal food products AGEs are added directly during the manufacturing process. AGEs are a considerable concern as they have been shown to contribute to the increasing prevalence of diet-related chronic inflammation found in animals and humans alike as well as their negative health consequences on cancer, diabetes and cognitive brain function.

Bridging the knowledge gap and taking advantage of progress in the human field regarding the detrimental effects of diet on health, may significantly improve the nutritional quality of the foods we currently feed our animal companions. By using canine and human comparative biology approaches, we may define AGEs as novel modifiable metabolites that may be targeted to augment risk reduction and represent a lifestyle bio-behavioral marker that can be targeted by dietary and lifestyle change.

Mentor Statement

To date (Dec 2020) I have mentored 3 Ph.D. and 14 M.S. students, the majority of which have gone on to further develop their research careers in academia or industry. I understand the importance of a successful research training program and an accompanying career mentoring plan for all trainee investigators. I create specific training programs for all individuals that I mentor. This is conceptually divided into four components: 1) a specific independent research project, 2) my role as a mentor and my mentoring experience and expectations, 3) participation in intra- and inter-mural research seminars, and 4) hands on training in the methods of clinical and translational research.

Publications (2015 - 2021)

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  1. Krisanits B, Schuster R, Randise J, Nogueira L, Turner DP, Findlay VJ. Advanced glycation end products in the food chain impact mammary gland dysfunction during puberty. J. Nutr.. Forthcoming;
  2. Krisanits B, Woods P, Cosh S, Nogueira L, Findlay VF, Turner DP. Advanced glycation end product consumption can promote prostate tumor growth in vivo. Can. Res. Forthcoming;
  3. Jiang WP, Wang X, Zhou Z, Turner DP, Lilly MB, Ou T. Differential circulating fungal microbiome in prostate cancer patients compared to healthy control individuals. Frontiers in Oncology. Forthcoming;
  4. Omofuma OO, Peterson LL, Turner DP, Merchant AT, Uribarri J, Steck SE. Dietary Advanced Glycation End-Products (AGEs) and Mortality After Breast Cancer in the Women’s Health Initiative (WHI). American Journal of Epidemiology. Forthcoming;
  5. Gregoski MJ, Newton J, Blaylock K, Smith S , Turner DP. Examination of the Effectiveness of the Healthy Empowered Active Lifestyles (HEAL) program on Advanced Glycation Endproducts. Int. J. Environ. Res. Public Health. Forthcoming;
  6. Omofuma OO, Turner DP, Peterson LL, Merchant AT, Zhang J, Steck SE. Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cancer Prev Res (Phila). 2020 Jul;13(7):601-610. doi: 10.1158/1940-6207.CAPR-19-0457. Epub 2020 Mar 13. PubMed PMID: 32169887; PubMed Central PMCID: PMC7335328.
  7. Peterson LL, Park S, Park Y, Colditz GA, Anbardar N, Turner DP. Dietary advanced glycation end products and the risk of postmenopausal breast cancer in the National Institutes of Health-AARP Diet and Health Study. Cancer. 2020 Jun 1;126(11):2648-2657. doi: 10.1002/cncr.32798. Epub 2020 Feb 25. PubMed PMID: 32097496; PubMed Central PMCID: PMC7220830.
  8. Ford ME, Bauza CE, Findlay VJ, Turner DP, Abraham LM, Moore LA, Magwood G, Alberg AJ, Gaymon K, Knight KD, Hilton E, Malek AM, Kramer RM, Peterson LL, Gregoski MJ, Bolick S, Hurley D, Mosley C, Hazelton TR, Burshell DR, Nogueira L, Mack F, Brown ET, Salley JD, Whitfield KE, Esnaola NF, Cunningham JE. BMI, physical activity, and breast cancer subtype in white, black, and Sea Island breast cancer survivors. Adv Cancer Res. 2020;146:83-102. doi: 10.1016/bs.acr.2020.01.005. Epub 2020 Mar 12. Review. PubMed PMID: 32241393.
  9. Krisanits B, Randise JF, Burton CE, Findlay VJ, Turner DP. Pubertal mammary development as a "susceptibility window" for breast cancer disparity. Adv Cancer Res. 2020;146:57-82. doi: 10.1016/bs.acr.2020.01.004. Epub 2020 Mar 9. Review. PubMed PMID: 32241392.
  10. Ou T, Zhou Z, Turner DP, Zhu B, Lilly M, Jiang W. Increased Preoperative Plasma Level of Microbial 16S rDNA Translocation Is Associated With Relapse After Prostatectomy in Prostate Cancer Patients. Front Oncol. 2019;9:1532. doi: 10.3389/fonc.2019.01532. eCollection 2019. PubMed PMID: 32010622; PubMed Central PMCID: PMC6974797.
  11. Walter KR, Ford ME, Gregoski MJ, Kramer RM, Knight KD, Spruill L, Nogueira LM, Krisanits BA, Phan V, La Rue AC, Lilly MB, Ambs S, Chan K, Turner TF, Varner H, Singh S, Uribarri J, Garrett-Mayer E, Armeson KE, Hilton EJ, Clair MJ, Taylor MH, Abbott AM, Findlay VJ, Peterson LL, Magwood G, Turner DP. Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention. Breast Cancer Res Treat. 2019 Feb;173(3):559-571. doi: 10.1007/s10549-018-4992-7. Epub 2018 Oct 27. PubMed PMID: 30368741; PubMed Central PMCID: PMC6394600.
  12. Nogueira LM. MicroRNA 204 Mediated Negative Regulation of the IGF2R Promotes Breast Cancer Progression and is a Potential Mechanism Driving Breast Cancer Disparity. Cancer Health Disparities. 2018; 2:e1. doi: 10.9777/chd.2018.10026.
  13. Turner DP, Findlay VJ. Biological Implications of Diet-Derived Advanced Glycation End Products on Carcinogenesis . In: Dietary AGEs and Their Role in Health and Disease. 1st Edition ed. Uribarri JJ, editor. United States: CRC Press/Taylor & Francis Group; 2017. Chapter 15; 14p.
  14. Turner DP. The Role of Advanced Glycation End-Products in Cancer Disparity. Adv Cancer Res. 2017;133:1-22. doi: 10.1016/bs.acr.2016.08.001. Epub 2016 Oct 12. Review. PubMed PMID: 28052818.
  15. Ford ME, Magwood G, Brown ET, Cannady K, Gregoski M, Knight KD, Peterson LL, Kramer R, Evans-Knowell A, Turner DP. Disparities in Obesity, Physical Activity Rates, and Breast Cancer Survival. Adv Cancer Res. 2017;133:23-50. doi: 10.1016/bs.acr.2016.08.002. Epub 2016 Oct 31. Review. PubMed PMID: 28052820; PubMed Central PMCID: PMC6598680.
  16. Tricarico R, Cortellino S, Riccio A, Jagmohan-Changur S, Van der Klift H, Wijnen J, Turner D, Ventura A, Rovella V, Percesepe A, Lucci-Cordisco E, Radice P, Bertario L, Pedroni M, Ponz de Leon M, Mancuso P, Devarajan K, Cai KQ, Klein-Szanto AJ, Neri G, Møller P, Viel A, Genuardi M, Fodde R, Bellacosa A. Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis. Oncotarget. 2015 Dec 15;6(40):42892-904. doi: 10.18632/oncotarget.5740. PubMed PMID: 26503472; PubMed Central PMCID: PMC4767479.
  17. Hughes FM Jr, Turner DP, Todd Purves J. The potential repertoire of the innate immune system in the bladder: expression of pattern recognition receptors in the rat bladder and a rat urothelial cell line (MYP3 cells). Int Urol Nephrol. 2015 Dec;47(12):1953-64. doi: 10.1007/s11255-015-1126-6. Epub 2015 Oct 22. PubMed PMID: 26490556; PubMed Central PMCID: PMC4774865.
  18. Turner DP. Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity. Cancer Res. 2015 May 15;75(10):1925-9. doi: 10.1158/0008-5472.CAN-15-0169. Epub 2015 Apr 28. Review. PubMed PMID: 25920350; PubMed Central PMCID: PMC4433613.
  19. McDonald LT, Russell DL, Kelly RR, Xiong Y, Motamarry A, Patel RK, Jones JA, Watson PM, Turner DP, Watson DK, Soloff AC, Findlay VJ, LaRue AC. Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia. 2015 May;17(5):434-48. doi: 10.1016/j.neo.2015.04.004. PubMed PMID: 26025666; PubMed Central PMCID: PMC4468366.
Information flyer to lower daily AGE intake

As our bodies use the sugars that we consume for energy, they generate waste chemicals known as Advanced Glycation End Products or AGEs for short. AGEs accumulate in the body as we grow older, which damages our tissues and organs and contributes to chronic diseases such as diabetes, Alzheimer's, cardiovascular disease, arthritis, cancer, and others.