Education:
- BS (1991) Zoology. University of Oklahoma; Norman, OK.
- DVM (2001). Oklahoma State University College of Veterinary Medicine; Stillwater, OK.
- Residency, Comparative Medicine (2004-2005). SUNY at Buffalo, Buffalo, NY.
- Postdoctoral Fellowship in Laboratory Animal and Comparative Medicine (2005-present). Wake Forest University School of Medicine.
Clinical Interests: Laboratory Animal and Comparative Medicine
Research Interests: Obesity, adipokine-mediated inflammation, type 2 diabetes, candidate gene analysis, differential gene expression between visceral and subcutaneous adipose tissue depots, macrophage infiltration into adipose tissue, vervet monkey model of obesity.
Current Research:
Obesity has become an epidemic in the U.S., as well as worldwide, and is a key risk factor for several major chronic diseases such as type 2 diabetes (T2D) and cardiovascular disease (CVD). Subclinical, systemic inflammation is increased in obese states and is thought to play an important role in the pathogenesis of both diseases. Adipose tissue is an important source of circulating inflammatory cytokines which represent a likely pathogenic link between obesity and insulin resistance (leading to T2D) and metabolic syndrome (a set of CVD risk factors). However, the timing of the onset of inflammation in T2D and CVD is uncertain. It is also unclear why pancreatic insulin production is sufficient in some obese humans or animals with insulin resistance, but not in others. The answer is almost certainly multifactorial, with interactions between environmental, genetic, and age-related components.
A closed, pedigreed colony of vervet monkeys (Chlorocebus aethiops) offers the potential for valuable and unique insight into these research questions. Like many species of Old World nonhuman primates (NHPs), vervets can develop spontaneous obesity on a standard controlled diet with subsets showing insulin resistance, T2D, and CVD. Further, the pattern of abdominal fat deposition, which is thought to be associated with greater mediation of inflammation, is similar to humans. Thus, NHPs, and this colony of vervets in particular with their relatively high percentage of obesity and insulin resistance, are excellent models for obesity and its related comorbidities. Controlled diet and housing conditions of colony rearing offer great potential to dissect the effects environmental factors have on inflammation and obesity that is not possible in human studies. Further, genetic analyses are possible with this colony as it has been fully pedigreed, one of only a few pedigreed NHP colonies in the world. Initial data generated in the Wagner lab has shown that heritability measures of obesity and obesity-related phenotypes are significantly heritable and are similar to published human values. Body Mass Index (BMI) is a predictable phenotypic trait in this colony and offspring BMI at 4-5 years of age can be predicted based on maternal BMI. This lays the foundation for central questions of my thesis project: Does allelic variation in certain candidate genes exist in vervets similar to humans? If so, are there significant associations with obesity and obesity-related phenotypes as in humans?
Working closely with Dr. Tim Howard in Human Genomics (who is on my committee and essentially my "co-mentor" for my thesis project), we are currently in the process of sequencing and genotyping various candidate genes in the vervet. The protein products of which are inflammatory cytokines and/or adipokines (cytokines produced by adipocytes) involved in the putative inflammatory cascade of obesity. Various single nucleotide polymorphisms (SNPs) of these candidate genes have been well documented in humans as well as associations between the SNPs and obesity and/or obesity-related phenotypic traits. The goals of my study are to initially sequence candidate genes to determine to what degree SNPs exist. Then, given sufficient evidence for allelic variation, genotype the entire pedigreed colony, which includes about 500 vervets as well as another 700 deceased vervets for which we have access to stored DNA. Secondly, cohorts based on life stage and maternal BMI will be measured for a set of circulating biomarkers and morphologic traits and assessed for allelic associations.
My specific aims are:
- Determine the allelic variation in certain cytokine and adipokine gene loci of Chlorocebus aethiops using DNA sequencing and SNP analysis;
- Determine if allelic associations exist with obesity, components of the metabolic syndrome or circulating biomarkers (inflammatory markers, lipids, blood pressure, glucose and insulin) using candidate gene analysis and;
- Determine the percentage identity with homologous human genes using bioinformatics.
Results from this study have the potential to genetically characterize, and thus further define, the vervet as a model of human obesity as well as provide insight into the evolutionary origins of T2D (for example, in regard to the “thrifty gene” hypothesis). If allelic associations are shown as I hypothesize, this would contribute to answering whether inflammation is a pathogenic link between obesity and its comorbidities. Furthermore, it will help address to what degree genotype can offer protection from or susceptibility to disease. Finally, implications for future studies would include: additional candidate gene analyses, linkage mapping, interventional studies based on genotype and, pharmacogenomics.
Publications:
Schaefer GB, Thompson JN, Bodensteiner JB, McConnell JM, Kimberling WT, Gay CT, Dutton WD, Hutchings DC, Gray SB. Hypoplasia of cerebellar vermis in neurogenetic syndromes. Annals of Neurology 1996;39:382-385.
Thompson JN, Gray SB, Hellack JJ. Linguini models of molecular genetic mapping and fingerprinting. The American Biology Teacher 1997;59:416-418.
Thompson JN, Woodruff RC, Gray SB, Hendrix GS, Hellack JJ. Cellulose acetate measurement of Adh allele frequencies is a simple exercise in population genetics. Drosophila Information Service 2000;83:205.
Posters/Abstracts:
SB Gray, TD Howard, CD Langefeld, GA Hawkins, AF Diallo, JD Wagner. Single nucleotide polymorphisms of the TNF-alpha gene in captive vervet monkeys (Chlorocebus aethiops). 30th Annual Meeting of the American Society of Primatologists (ASP), Winston Salem, NC, June 2007. Am J Primatol, 2007, 69(suppl); abstr 61.
JD Wagner, L Zhang, K Kavanagh, SB Gray, MR Adams, JR Kaplan. Effects of sex hormones and soy isoflavones on obesity and insulin resistance in cynomolgus monkeys. 30th Annual Meeting of the American Society of Primatologists (ASP), Winston Salem, NC, June 2007. Am J Primatol, 2007, 69(suppl); abstr 71.
SB Gray, JA Cann, JA Trybus, K Kavanagh, JD Wagner. Characterization of clinical pathology and pancreatic islet pathology in captive, spontaneously diabetic vervet monkeys (Chlorocebus aethiops). 58th Annual Meeting of the American Association of Laboratory Animal Science (AALAS), Charlotte, NC, October 2007.
SB Gray, TD Howard, CD Langefeld, GA Hawkins, AF Diallo, JD Wagner. Single nucleotide polymorphisms and comparative sequence analysis of the TNF-alpha gene in a pedigreed colony of vervet monkeys (Chlorocebus aethiops). 57th Annual Meeting of the American Society for Human Genetics (ASHG), San Diego, CA, October 2007.
Abstracts:
SB Gray, TD Howard, GA Hawkins, AF Diallo, JD Wagner. Amylin gene sequence of the amyloidogenic region in the vervet monkey (Chlorocebus aethiops), Diabetes 2007 Supplement (abstr).