Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction

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PROJECT SUMMARY/ABSTRACT This proposal presents a two-year supplement award to the R01 titled “Role of 12-lipoxygenase and 12- HETE signaling in beta-cell dysfunction,” for the research career development plan of Isabel Casimiro, MD, PhD, who is currently an Instructor of Medicine at the University of Chicago. The outlined proposal builds on the candidate's previous graduate research in macrophage function and post-doctoral experience in adipose tissue biology in order to expand the understanding on the interplay between macrophages and adipose tissue. Her primary mentor will be Dr. Raghavendra Mirmira, a physician scientist and Director of the Translational Research Center who has 10 years of experience working on the 12/15-lipoxygenase (LOX) pathway in pancreatic beta cells. Other mentors will include Dr. Lev Becker, who specializes in the macrophage metabolic “MMe” activation phenotype, Dr. Matthew Brady who is an expert in adipose tissue biology, and Dr. Laura Alonso, a physician scientist who specializes in diabetes and pancreatic biology. The macrophage is a major player in perpetuating the inflammatory phenotype that contributes to insulin resistance and obesity. The classification of macrophages as polarizing towards a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype has failed to capture the heterogeneity of macrophages or the scope of their function in metabolic disease. New evidence suggests that macrophages can be polarized towards a state of “metabolic activation” (MMe) that is distinct from M1 activation by macrophage surface marker expression, but also results in proinflammatory cytokine production. Very few studies have explored metabolic macrophage polarization in the setting of obesity development. The 12/15-LOX enzyme yields bioactive inflammatory mediators and is activated by hyperglycemia and cytokine damage to promote macrophage inflammatory activity. How the 12/15-LOX pathway affects macrophage polarization towards M1 activity in vivo or if it is involved in MMe activation in the setting of obesity is unknown. I hypothesize that 12/15-LOX promotes macrophage migration, and polarization towards metabolic and proinflammatory activity that contributes to obesity and insulin resistance. I will leverage an inducible, targeted deletion model of Alox15 to test this hypothesis in the following aims: (1) Define the effects of macrophage 12/15-LOX during the development of obesity and insulin resistance in mice. (2) Determine if human macrophages depend on 12/15-LOX for polarization in the setting of metabolic disease. These studies will provide insights into how macrophage inflammatory pathways affect the development of obesity and will provide evidence of human translatability and novel therapeutic avenues in the treatment of obesity and type 2 diabetes. The proposed experiments and didactic experiences will position the candidate with a unique set of skills that will enable her transition to independence as a physician scientist in the field of immunometabolism.