This is an application by Dr. Rachel McMahan for the Mentored Research Scientist Development Award (K01). Dr. McMahan is an Instructor in the Department of Gastroenterology at the University of Colorado Anschutz Medical Campus. The candidate's career goal is to become an established independent investigator with a research team dedicated to understanding the role of the immune response in non-alcoholic fatty liver disease (NAFLD) and other obesity-related diseases. NAFLD affects a large proportion of the American population and can lead to steatohepatitis, cirrhosis and eventual liver failure. In preliminary studies it was determined that administration of a bile acid (BA) receptor agonist to obese db/db mice significantly improved the histologic features of NAFLD and decreased liver inflammation. Interestingly, the treatment led to considerable increases in the Ly6Clow monocyte population within the liver and an increase in IL-10 production by monocytes. While, Ly6Chigh monocytes have recently been implicated as important mediators for obesity-associated liver inflammation, it has been suggested that Ly6Clow monocytes may inhibit the inflammatory response and differentiate into alternatively activated macrophages (AAM). The studies proposed here will further evaluate the effects of BA activation on monocytes and establish the role of these cells in NAFLD.
Aim 1 will determine if BA receptor activation alters monocyte differentiation, survival and/or migration to the liver.
Aim 2 will evaluate if monocytes can in turn protect against NAFLD and Aim 3 will investigate if IL-10 plays a role in disease improvement. These studies will provide novel insight in to how BA receptor activation coordinates the immune phenotype of monocytes and macrophages and will help in identifying potential targeting strategies for treatment of NAFLD. The candidate will utilize the results from these studies to develop new hypotheses and apply for R01 support. Dr. McMahan has extensive training in immunology and this award will provide her with the opportunity to expand her scientific expertise into the areas of metabolism and obesity. She will be mentored by Dr. Hugo Rosen, an expert in the field of liver immunology with an excellent funding history and publication record. In addition, she will be co-mentored by Dr. Moshe Levi who has extensive experience in obesity, metabolism and nuclear receptor biology. She has assembled a strong interdisciplinary advisory committee that includes experts in the areas of murine macrophage biology (Dr. Cynthia Ju) and nuclear receptors (Dr. Suchy). This committee has helped Dr. McMahan develop a strong career development plan and their expertise will allow for her to successfully transition into a career as independent scientist in this exciting area of interdisciplinary research.
Obesity can lead to number of clinically relevant health problems including non-alcoholic fatty liver disease (NAFLD). NAFLD occurs when there is an increase in fat within the liver leading to liver inflammation, scar tissue accumulation and eventual loss of liver function, a condition known as cirrhosis. Our studies aim to determine the role of various immune cell types in the development of liver disease and help in the design of strategies for treatment of NAFLD.
|McGettigan, Brett M; McMahan, Rachel H; Luo, Yuhuan et al. (2016) Sevelamer Improves Steatohepatitis, Inhibits Liver and Intestinal Farnesoid X Receptor (FXR), and Reverses Innate Immune Dysregulation in a Mouse Model of Non-alcoholic Fatty Liver Disease. J Biol Chem 291:23058-23067|
|McMahan, Rachel H; Porsche, Cara E; Edwards, Michael G et al. (2016) Free Fatty Acids Differentially Downregulate Chemokines in Liver Sinusoidal Endothelial Cells: Insights into Non-Alcoholic Fatty Liver Disease. PLoS One 11:e0159217|
|McMahan, Rachel H; Wang, Xiaoxin X; Cheng, Lin Ling et al. (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288:11761-70|