Turner-Findlay Collaboration

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.

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:
https://www.youtube.com/watch?v=LvwMXqyrKG0
https://www.youtube.com/watch?v=FH2ktQSsacw
https://www.postandcourier.com/news/what-are-advanced-glycation-end-products-ages-explained-in-90-seconds/video_a18f944c-f98b-11e9-86a2-833745f3cc02.html
https://musc.bcst.md/videos/advanced-glycation-end-products-a-lifestyle-biomarker

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 and 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; and 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 and diet: their impact on animal companion well-being and 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.

I have mentored many junior faculty members, Ph.D.’s M.S., college and high school students, many of which have gone on to further develop their research careers in the clinic, academia or industry. I understand the importance of a successful research training program and an accompanying career mentoring plan for all trainee investigators. As a matter of course, 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.