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Dr. Webster's research lies in the general area of Endocrinology, Neuroendocrinology and Metabolism and addresses the mechanisms of intracellular signaling in response to hormonal and metabolic stimuli. He has a long-standing interest in the insulin receptor and its downstream signaling. His lab has shown how a single insulin receptor gene gives rise to two distinct insulin receptors and how these receptors differ in regulating physiological processes. He identified the splicing factors responsible for alternative splicing of the gene that gives rise to the two receptor isoforms. His lab created hepatocyte-specific knockouts of SRSF3 and SRSF1 and found that loss of SRSF3, but not SRSF1, disrupted hepatic architecture, impaired hepatocyte maturation, altered glucose and lipid homeostasis and eventually led to hepatocellular carcinoma (HCC) as mice age. Tumor development is preceded by chronic liver disease with progressive non-alcoholic fatty liver disease (NAFLD), then non-alcoholic steatohepatitis (NASH) and fibrosis. They showed that SRSF3 protein expression was decreased in human liver samples with NAFLD, NASH or cirrhosis and ultimately in non-viral HCC. Subsequently, they showed that lipid excess caused proteosomal degradation of SRSF3 through a novel NEDD8-mediated pathway. Excitingly, prevention of SRSF3 degradation in vivo protected mice from hepatic steatosis, fibrosis and inflammation suggesting that loss of SRSF3 may be an initiating event in progressive liver disease. The lab is currently investigating the pathway for SRSF3 degradation in fatty liver disease and identifying the role for E3-ligases in post-translational regulation of SRSF3.
A second project is focused on the link between time-restricted feeding, obesity and cancer. Obesity is a risk factor for many cancers and the evidence for the obesity-breast cancer connection is particularly strong in post-menopausal women although the mechanisms remain poorly understood. His lab confirmed that HFD-induced or genetic obesity enhances tumor growth using orthotopic injection of syngeneic breast cancer cells. They showed that time-restricted feeding (TRF), a form of intermittent fasting in which food intake is limited to a particular number of hours per day, causes a dramatic reduction in hepatic steatosis and metabolic parameters and inhibits breast cancer growth. Mechanistically, they showed that the reduction in circulating insulin levels was the origin of the beneficial effect of TRF on tumor growth. Recent experiments have shown that TRF is equally effective against NASH-driven liver cancer.
In a third collaborative project with Dr. Eyal Raz's lab, he has uncovered a new pathway in CD11c+ dendritic cells (DC) that controls T helper cell differentiation into the Th17 and Th2 lineages. Deletion of Gnas in CD11c+ cell (Gnas/CD11c) causes the development of spontaneous airway inflammation that mimics the pathology of eosinophilic Th2-biased asthmatic patients. They showed that cAMP-PKA-CREB signaling regulates conventional type-2 Dendritic Cells (cDC2s), but not cDC1s, and reprograms their Th17-inducing properties via repression of the IRF4 and KLF4 transcription factors. Interestingly, these KO mice are resistant to diet-induced obesity. The mice do not develop hepatic steatosis, are insulin sensitive, consume more oxygen, and have slightly higher body temperature despite having the same food intake. They have shown that this is due to CD11c+ dendritic cells not macrophages, and the DCs reprogram white adipose tissue, causing beigeing and increased mitochondrial uncoupling.