Validation of small molecule 12-lipoxygenase inhibitors in metabolic disease

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 DESCRIPTION (provided by applicant): The crude prevalence of pre-diabetes and diabetes in the US is a staggering 40%. It is now widely recognized that deficiencies of ß cell mass and/or function are central in the transition from impaired glucose tolerance to frank diabetes in virtualy all forms of diabetes. In the setting of obesity and insulin resistance, the genesis of insulin secretory defects is multifactorial, and includes not only inflammatory pathways intrinsic to the cell, but also a network in which proinflammatory signals from the adipocyte and macrophage feed forward to impair ß cell function. This convergence on ß cell health suggests that common pathways of inflammation can be manipulated to protect ß cells in both type 2 diabetes (T2D) and type 1 diabetes (T1D). This grant application is a partnership between the laboratories of Drs. R. Mirmira and J. Nadler - with close collaborations with Dr. T. Holman and the NIH Chemical Genomics Center (NCGC) - and will focus on the early stage pharmacologic validation of novel human 12/15-lipoxygenase (12-LO) inhibitors for the prevention or reversal of metabolic disease. 12-LO catalyzes the oxygenation of cellular poly-unsaturated fatty acids to form lipid by-products such as 12-HPETE and 12-HETE, which impose inflammatory and oxidative stress within ß cells, causing their dysfunction and death. The strength of this application is the collaborative effort between MPIs and collaborators, who collectively will bring their expertise and unique reagents - including knockout mouse models, selective lead inhibitor compounds ML127 and ML355, and primary human cells - to bear on the preclinical validation of small molecule inhibitors of 12-LO in diabetes. We will test the hypothesis that inhibition of 12-LO with lead small molecule inhibitors will result in the prevention or mitigation of hyperglycemia in the setting of insulin resistance, T2D, and T1D. We propose the following 3 aims: Aim 1: Determine the efficacies and mechanism of lead 12-LO inhibitors in prevention and treatment of insulin resistance and T2D. Aim 2: Assess the efficacies of lead 12-LO inhibitors in prevention and treatment of ß cell dysfunction and death in T1D. Aim 3: Interrogate next generation 12-LO inhibitors potencies and molecular mechanisms in human islets. The strength of our approach lies in the unique reagents in our possession, notably, novel specific 12-LO inhibitors and conditional knockout mice. The primary impact of this proposal will be the identification and early-stage preclinical validation of 12-LO inhibitors for use in the prevention or treatment of T2D and T1D