Deficiencies in islet ?-cell function and/or mass are central in the transition from impaired glucose tolerance to frank diabetes in the setting of both type 1 and type 2 diabetes. The lipoxygenases (LOXs) represent a family of enzymes that catalyzes the oxygenation of cellular poly-unsaturated fatty acids to form lipid inflammatory mediators in ?-cells. The eicosanoid product of 12-LOX activity, 12-hydoxyeicosatetraenoic acid (12-HETE), imposes inflammatory and oxidative stress within ? cells. A challenge in lipoxygenase biology, however, is that humans and mice express different isoforms of 12-LOX in ? cells (encoded by ALOX12 and Alox15, respectively), with each isoform exhibiting different active-site characteristics. The strength of this application is the collaborative effort between Multi-PIs Drs. R. Mirmira (an expert in islet inflammation pathways) and R. Kulkarni (an expert in growth factor signaling in the islet), and coinvestigator J. Nadler (an expert in eicosanoid biology), who will collectively bring their expertise and unique reagents?including knockout and human gene knock-in mouse models that show human isoform activation, human 12-LOX-selective inhibitors, and primary human cells?to bear on the biology of 12-LOX and its inflammatory products. We hypothesize that during insulin resistance the activation of 12-LOX in ?-cells promotes ? cell dysfunction through receptor-mediated signaling by its downstream product 12-HETE. To test this hypothesis, we propose the following specific aims:
Aim 1 : Elucidate the molecular mechanisms linking ?-cell insulin resistance to 12-LOX activity and cellular dysfunction.
Aim 2 : Determine the contribution of 12-LOX activity to ? cell dysfunction in the setting of insulin resistance in vivo.
Aim 3 : Determine the role of the 12-HETE receptor GPR31 in mediating ?-cell dysfunction downstream of 12-LOX. Until now, tools and reagents to interrogate the biology of human 12-LOX and 12-HETE did not exist. The primary impact of this proposal will be to set the stage for the expectations of therapeutically targeting the human 12-LOX pathway in insulin resistance/?-cell dysfunction, and to identify a potential new target in the 12-HETE G protein-coupled receptor GPR31.
Dysfunction and death of the insulin-producing ?-cell underlies virtually all forms of diabetes, and the protection of ?-cells represents an approach to the treatment of diabetes that has yet to be exploited. The 12-LOX pathway represents an attractive target for protection of ?-cells, since inhibitors of this pathway have been developed. This proposal will provide a better understanding of how the 12-LOX pathway can be manipulated to protect ?-cells.
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