Person: Swindell, William
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Swindell
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William
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Swindell, William
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Publication SRT1720 improves survival and healthspan of obese mice(Nature Publishing Group, 2011) Minor, Robin K.; Baur, Joseph A.; Gomes, Ana P.; Ward, Theresa M.; Csiszar, Anna; Mercken, Evi M.; Abdelmohsen, Kotb; Shin, Yu-Kyong; Canto, Carles; Scheibye-Knudsen, Morten; Krawczyk, Melissa; Irusta, Pablo M.; Martín-Montalvo, Alejandro; Hubbard, Basil Paul; Zhang, Yongqing; Lehrmann, Elin; White, Alexa A.; Price, Nathan Loftus; Swindell, William; Pearson, Kevin J.; Becker, Kevin G.; Bohr, Vilhelm A.; Gorospe, Myriam; Egan, Josephine M.; Talan, Mark I.; Auwerx, Johan; Westphal, Christoph H.; Ellis, James L.; Ungvari, Zoltan; Vlasuk, George P.; Elliott, Peter J.; Sinclair, David; de Cabo, RafaelSirt1 is an NAD1-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1a-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.Publication Transcriptional profiles of leukocyte populations provide a tool for interpreting gene expression patterns associated with high fat diet in mice(Public Library of Science, 2010) Swindell, William; Johnston, Andrew; Gudjonsson, Johann E.Background: Microarray experiments in mice have shown that high fat diet can lead to elevated expression of genes that are disproportionately associated with immune functions. These effects of high fat (atherogenic) diet may be due to infiltration of tissues by leukocytes in coordination with inflammatory processes. Methodology/Principal Findings: The Novartis strain-diet-sex microarray database (GSE10493) was used to evaluate the hepatic effects of high fat diet (4 weeks) in 12 mouse strains and both genders. We develop and apply an algorithm that identifies “signature transcripts” for many different leukocyte populations (e.g., T cells, B cells, macrophages) and uses this information to derive an in silico “inflammation profile”. Inflammation profiles highlighted monocytes, macrophages and dendritic cells as key drivers of gene expression patterns associated with high fat diet in liver. In some strains (e.g., NZB/BINJ, B6), we estimate that 50–60% of transcripts elevated by high fat diet might be due to hepatic infiltration by these cell types. Interestingly, DBA mice appeared to exhibit resistance to localized hepatic inflammation associated with atherogenic diet. A common characteristic of infiltrating cell populations was elevated expression of genes encoding components of the toll-like receptor signaling pathway (e.g., Irf5 and Myd88). Conclusions/Significance: High fat diet promotes infiltration of hepatic tissue by leukocytes, leading to elevated expression of immune-associated transcripts. The intensity of this effect is genetically controlled and sensitive to both strain and gender. The algorithm developed in this paper provides a framework for computational analysis of tissue remodeling processes and can be usefully applied to any in vivo setting in which inflammatory processes play a prominent role.Publication Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis(Public Library of Science, 2011) Swindell, William; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.