Dr. Oldham focuses on the nutrient sensing Insulin-TOR pathway as it relates to obesity, aging, and cancer.
Dr. Oldham received his Ph.D. in Pharmacology from University of North Carolina, Chapel Hill in 1997.
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Bunched, the Drosophila homolog of the mammalian tumor suppressor TSC-22, promotes cellular growth.
Gluderer S, Oldham S, Rintelen F, Sulzer A, Schütt C, Wu X, Raftery LA, Hafen E, Stocker H
BMC Dev Biol. 2008;8:10
Drosophila aging 2006/2007.
Shaw P, Ocorr K, Bodmer R, Oldham S
Exp Gerontol. 2008 Jan;43(1):5-10
Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity.
Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R, Oldham SM
Cell Metab. 2006 Aug;4(2):133-42
TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model.
Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB
Curr Biol. 2006 Feb 7;16(3):230-41
The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima.
Dekanty A, Lavista-Llanos S, Irisarri M, Oldham S, Wappner P
J Cell Sci. 2005 Dec 1;118(Pt 23):5431-41
Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control.
Oldham S, Hafen E
Trends Cell Biol. 2003 Feb;13(2):79-85
Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB.
Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E
Science. 2002 Mar 15;295(5562):2088-91
Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.
Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L
Science. 2001 Apr 6;292(5514):104-6
Genetic control of size in Drosophila.
Oldham S, Böhni R, Stocker H, Brogiolo W, Hafen E
Philos Trans R Soc Lond B Biol Sci. 2000 Jul 29;355(1399):945-52
Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin.
Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E
Genes Dev. 2000 Nov 1;14(21):2689-94
Sean Oldham's Research Focus
Diet, Nutrient, and Environmentally Regulated Genes and Pathways in Obesity, Aging, and Cancer
Obesity has grown to epidemic proportions globally, with more than 1 billion adults overweight and 300 million of them considered clinically obese. Obesity has been shown to be a major contributor to chronic diseases, such as heart disease, diabetes, and cancer with the incidence of these diseases increasing with age. Yet, surprisingly still little is known about the genetic and molecular mechanisms involved in diseases that are correlated with increased lipid consumption. The role of aging in contributing to these diseases is also not well understood. The prevalence of obesity in the United States and the rest of the world has dramatically increased in a relatively short time period. Poor diets and diets high in fat, in combination with sedentary lifestyles are likely the primary causes of obesity in the western world. Therefore, investigating the effects of high fat dietary intake is an important step in understanding the factors that contribute to the increase in obesity and in turn the secondary diseases caused by it.
Obesity and aging have been established as a major contributor for developing heart disease, diabetes, and cancer. However, the genetics of the obesity-aging relationship is largely unknown and thus in need of investigation. Progress in obesity research is also hampered by the complexity in genetic/metabolic and environmental interactions. Therefore, it would be beneficial if one could study the central aspects of High Fat Diet (HFD)-induced obesity (ie. the molecular control of dietary fat accumulation) and aging (ie. the molecular pathways that control aging) in a simplified system. Drosophila has recently emerged as a powerful tool for discovering not only the conserved genetic network of metabolism as well as the central pathways regulating growth and aging. We aim to understand the genetic interplay of metabolism, growth, and aging by focusing on the nutrient sensing Insulin-TOR pathway as it relates to these diseases.
Areas of Research:
1. Role of Genes and Pathways in HFD Obesity and Heart Disease
An obstacle in the progress of the study of obesity is the complexity of mammalian genetics and their metabolic systems. Therefore, we are utilizing the genetic potential of Drosophila as a simplified model for the investigation of the central metabolic mechanisms of High Fat Diet-induced obesity and its relation to heart disease (in collaboration with Dr. Rolf Bodmer). By using Drosophila we are testing how genetic manipulation of novel lipid metabolic signaling pathways can modulate heart structure and function (Luong et al., 2006).
2. Role of Diet and Nutrition in Gut/Intestinal Stem Cell Function and Aging
We have preliminary data showing that increasing age significantly increases triglyceride accumulation and shows detrimental effects on Gut-Intestinal Stem Cell (ISC) structure and function in the Drosophila genetic model system. We are examining these date in light of the cancer-aging hypothesis which posits that aging is a trade-off due to cancer suppression. Drosophila is an established model to study aging, because the basic aging functions are evolutionarily conserved. Drosophila is also the simplest genetic model with a gut that has conserved structure and function. This makes Drosophila unique for studying the pathways that regulate aging and their effects on Gut-ISC function both intrinsically within the ISCs and within the niche (stroma) at the cellular level.
3. Novel Genes and Tissue Communication in Diabetes
Drosophila has recently emerged as a simplified model for studying lipid and glucose metabolism, which demonstrates that the basic metabolic functions are evolutionarily conserved (Luong et al., 2006). The thrifty gene hypothesis suggests that certain gene variants were selected during evolutionarily recent times of famine and that these genes are now contributing to the obesity and diabetes epidemic. We are using various genetic approaches to identify these factors. Drosophila is also the simplest genetic model with insulin-TOR signaling (Oldham and Hafen, 2003), thus making it ideal for identifying novel genetic components and studying their autonomous and non-autonomous contributions to insulin sensitivity in a Drosophila model of Type 2 Diabetes.
About Sean Oldham
Sean Oldham received his early training at Revelle College, UCSD. Dr. Oldham earned his Ph.D. in Pharmacology from the University of North Carolina, Chapel Hill with Dr. Channing Der in 1997. He then trained as a postdoctoral fellow from 1998 - 2002 in developmental and physiological genetics at the Zoological Institute under Professor Ernst Hafen in Zurich, Switzerland.