This application is responsive to RFA-RM-19-011 and will focus on a poorly characterized GPCR in the Illuminating the Druggable Genome (IDG) database known as GPR31 in the context of diabetes. Over the past decade, our laboratory has focused on inflammation and the cellular response to inflammation as a central mechanism that contributes to ?-cell dysfunction and death type 1 diabetes (T1D) and type 2 diabetes (T2D). Specifically, our laboratory has demonstrated that 12-lipoxygenase (12-LOX), an enzyme involved in arachidonic acid metabolism and expressed in ?-cells, is activated in the context of ?-cell inflammation and produces the eicosanoid 12-S-hydroxyeicosatetraenoic acid (12(S)-HETE). 12(S)-HETE generates endoplasmic reticulum (ER) and oxidative stress in ? cells, but the mechanism through which this occurs has remained elusive. Deletion of the gene encoding 12-LOX in mice (Alox15), either conditionally in islets or globally, leads to protection from spontaneous type 1-like diabetes in NOD mice and obesity-induced type 2- like diabetes in high fat-fed mice. GPR31 has recently been de-orphaned and identified as the 12(S)-HETE receptor. We have generated congenic Gpr31b-/- mice on the C57BL6/J background through traditional ES cell cloning. Preliminary data suggest that Gpr31-/- mice are viable and metabolically normal, similar to Alox15- /- mice, however it remains to be determined if GPR31 mediates the effects of 12-LOX under diabetogenic conditions in ?-cells. In this proposal, we will generate preliminary data supporting the potential role of GPR31 as a key mediator of inflammation-induced ?-cell dysfunction and death, and the data and resources generated from this proposal will be made available to the Resource Dissemination and Outreach Center (RDOC) of the IDG program. This grant proposal continues a longstanding and productive collaboration between Drs. S. Tersey and R. Mirmira, who are co-located at the University of Chicago. The combined expertise of Dr. Mirmira in ? cell signaling cascades and Dr. Tersey in animal models of diabetes are synergistic towards the completion of this pilot proposal. Our Team will test the hypothesis that GPR31 promotes ?-cell inflammatory signaling and contributes to ?-cell dysfunction and death in the setting of diabetes. To test this hypothesis, the following two aims will be achieved within the timeframe allotted to this RFA:
Aim 1 : Elucidate the role of GPR31 in mediating the effects of diabetogenic inflammation and 12(S)-HETE in islets.
Aim 2 : Characterize the metabolic effects of GPR31 in vivo under normal and pro-inflammatory conditions. The primary impact of this proposal is the determination of whether GPR31 is a suitable target for drug development in the context of diabetic inflammation.

Public Health Relevance

This application is responsive to RFA-RM-19-011 and will focus on a poorly characterized GPCR in the Illuminating the Druggable Genome (IDG) database known as GPR31 in the context of diabetes. We will generate preliminary data supporting the potential role of GPR31 as a key mediator of inflammation-induced ?- cell dysfunction and death, and the data and resources generated from this proposal will be made available to the Resource Dissemination and Outreach Center (RDOC) of the IDG program.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Small Research Grants (R03)
Project #
1R03TR003381-01
Application #
10047529
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sharma, Karlie Roxanne
Project Start
2020-08-19
Project End
2021-07-31
Budget Start
2020-08-19
Budget End
2021-07-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637