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

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $228,585

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10338534
- **Project number:** 3R01DK105588-07S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** ROHIT N. KULKARNI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $228,585
- **Award type:** 3
- **Project period:** 2015-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338534

## Citation

> US National Institutes of Health, RePORTER application 10338534, Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction (3R01DK105588-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10338534. Licensed CC0.

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