ROLE OF OXIDIZED OMEGA-6 FATTY ACID METABOLITES IN DIABETIC NEUROPATHY

Type 2 diabetes (T2D) afflicts nearly 30 million individuals in the US, with at least 50% suffering from neurologicalcomplications that comprise diabetic neuropathy (DN). The metabolic changes in T2D produce substantialperipheral nerve damage that manifests commonly as debilitating numbness and neuropathic pain. Progressionof the nerve damage often leads to loss of sensation that can compromise patients? ability to execute daily tasksand care for themselves, while also increasing risk of severe injury. No effective treatments for DN are availablefor patients, who instead must rely on symptom management options that are marginally effective and haveburdensome side effect profiles. Fundamental research into novel mechanisms of DN is critically needed to helpidentify effective treatments. Recent clinical studies identified an unprecedented association between DN anddiabetic dyslipidemia. However, there are substantial gaps in knowledge regarding the mechanisms by whichdyslipidemia regulates DN. Oxidized metabolites of omega-6 polyunsaturated fatty acids (PUFAs) have beenshown to activate and/or sensitize nociceptors in acute and inflammatory pain conditions via direct activation ofTRPV1 and TRPA1. However, no studies have evaluated their role in DN. Our central hypothesis is that T2D-associated neuropathic pain is due to oxidation of omega-6 PUFAs into neuronally-active metabolites. To testthe hypothesis, we will: (1) determine the effects of T2D on omega-6 PUFA-induced activation or sensitizationof peripheral afferent neurons, and (2) identify prominent oxidized lipid species that contribute toactivation/sensitization of peripheral afferent neurons in T2D. This proposal will provide new insight into the roleof oxidized lipids in DN and will test for a causative link between aberrant omega-6 PUFA oxidation andperipheral afferent neuron dysfunction in T2D. These studies may yield a novel mechanism of how diabeticdyslipidemia alters peripheral afferent neuron function to produce neuropathic pain, which also includesidentification of new targets for an effective treatment of DN.