Friday, April 26, 2024
4/26/2024
ABSTRACT Diabetic neuropathy is the most common complication of diabetes, affecting ~ 50% of obese individuals with type II diabetes. Recent clinical and biological evidence indicate that painful type II diabetic neuropathy is highly associated with lipids, but the molecular and cellular neurophysiology underlying these observations is not known. Recent studies comparing dysregulated pathways in the peripheral nervous system (PNS) of individuals with type II diabetic neuropathy highlighted alterations in lipid-sensor nuclear receptor, suggesting a novel possible physiological basis for diabetic neuropathy. Our additional preliminary data suggest that nuclear receptor LXRs expressed in sensory neurons may be involved. This project combines in vivo and in vitro approaches to 1) study LXRs direct activation and as well as the downstream pathways regulated by lipids in sensory neurons, 2) determine whether the LXR pathway contributes to type II diabetic neuropathy in sensory neurons using a neuronal-specific deletion mouse model and high fat diet (HFD)-induced neuropathy models (cre-lox model), 3) to determine if LXR agonist protect against HFD induced neuropathy by regulating pathway(s) in the DRG small sensory neurons (RiboTag model). The central unifying hypothesis is that activation of LXRs in PNS neurons regulates downstream LXR-dependent program to maintain normal PNS function in the face of high-fat nutrition. Chronic rich lipid diets are expected to induce LXR signaling alterations that lead to PNS dysfunction. These studies will begin to decipher the cellular, molecular, and physiological role of lipid-sensor nuclear receptors in peripheral neurons in a type II diabetic mouse model. The results are expected to inform future mechanistic research and drug development aimed at addressing the unmet clinical need to treat neuropathy induced by obesity and its major complication, type II diabetes.
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