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GRK 1482 Jahrbuch 2011-2014

Publications [1] Swinburn BA, Caterson I, Seidell JC, James WP. Diet, nutrition and the prevention of excess weight gain and obesity. Public Health Nutrition. 2007, 7(1a). [2] Quante, M, Bhagat G, Abrams JA, Marache F, Good P, Lee MD, Lee Y, Friedman R, Asfaha S, Dubeykovskaya Z, Mahmood U, Figueiredo JL, Kitajewski J, Shawber C, Lightdale CJ, Rustgi AK, Wang TC). Bile Acid and In- flammation Activate Gastric Cardia Stem Cells in a Mouse Model of Barrett-Like Metaplasia. Cancer Cell. 2012, 21(1): 36-51. [3] Everhart JE, Ruhl CE. Burden of Digestive Diseases in the United States Part 1: Overall Upper Gastrointestingal Diseases. Gastroenterology. 2009, 136(2): 376-386. PhD FELLOWS GRK Progress Report 2011-2014 | Page 49 Aim We hypothesize that the over-expression of the cytokines IL- 1B and IL-6 play a role in the regulation of body weight in the IL-1Beta mouse model. Thus, the aims of our study are i) to conduct a detailed, long-term, metabolic phenotypic analysis of the model, ii) examine the differences in gut microbiome po- pulations between experimental locations (New York, USA and Freising, Germany), iii) examine the effects of High Fat feeding in relation to disease progression and cancer development in this model. Methods and Results Observations of the IL-1Beta model in NY showed signifi- cant increases in body weight as the mouse aged and deve- loped BE and EAC between 12 to 15 months of age, housed in an SPF(clean) facility. In Freising, mice were housed at the VAT(dirty) facility and feed a high fat diet (HFD) for 8-10 months. While these mice did not appear to significantly increase in body weight, the progression of BE to EAC appeared to be accelerated by the HFD. Similar results are being observed in the SPF(clean) facility in Freising as well. Based on these observations, our newly reassessed aims are to i) to conduct a detailed, long-term, metabolic phenotypic ana- lysis of the model. This will involve conducting metabolic mea- surements including body weight, body temperature, fat and lean mass distribution, direct and indirect calorimetric mea- surements, food, drink and activity measurements and gluco- se tolerance test. Upon sacrifice, endocrine analysis, as well as organ and tissue sampling will be conducted to compare the metabolic phenotype to that of their wild type littermates. Due to differing observation between the NY and Freising facili- ties, we will ii) examine the differences in gut microbiome popu- lations between experimental locations. 16S rRNA-based ana- lysis of fecal and cecal bacteria will be conducted to decipher if the drastically different phenotypes observed between NY and Freising might be due to different dominant strains of intestinal microflora. Samples from IL-1Beta mice and their wild type will be analyzed As obesity and EAC appear to be so closely linked, we will also iii) examine the effects of High Fat feeding in relation to disease progression and cancer development. This will involve high fat feeding of IL-1Beta mice and their wild-type littermates over the course of 12 to 15 months. Mice will be observed for changes in body weight. Additionally, we will conduct a thorough analysis at several times points (3,6,9 months) to monitor and rate the progression of BE to EAC, Outlook Given the enormous clinical and public health burden imposed by obesity, it is our goal to understand the relationship between inflammation, obesity and diet in this model of BE and EAC. Furthermore, we plan to re-derive the different transgenic mice in a germ free facility in order to analyze the role of the microbi- ome on IL-1╬▓ related obesity in more detail. Figure1: Immunohistochemistry showing evidence of dysplasia and Barrett esophagus in the cardia and esophagus of a 47week old female IL-1Beta mouse. Figure2: Immunohistochemistry showing evidence of severe inflammation in the liver of a 47week old female IL-1Beta mouse. as well as any changes in inflammation levels in terms of cyto- kines and hormones associated with obesity and EAC, glucose tolerance levels and feeding and drinking behavior. Supervisors Prof. Dr. Ronald M. Schmid I TUM I Klinikum rechts der Isar I Internal Medicine II Dr. Michael Quante I TUM I Klinikum rechts der Isar I Internal Medicine II Prof. Dr. Dirk Haller I TUM I Nutrition and Immunology Start of project: September 2011 Academic background: Studies of Food Science and Technology at University of California, Davis, USA

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