Nuclear lipid-sensor in Type II Diabetic Neuropathy

摘要 糖尿病性神经病变是糖尿病最常见的并发症，影响~ 50%的肥胖个体 患有II型糖尿病最近的临床和生物学证据表明，疼痛性II型糖尿病神经病变 与脂质高度相关，但这些观察结果背后的分子和细胞神经生理学 是未知的。最近的研究比较了周围神经系统（PNS）中的失调通路， 2型糖尿病神经病变的个体突出了脂质感受器核受体的改变，提示 糖尿病神经病变的一种新的可能的生理基础。我们额外的初步数据表明， 可能涉及感觉神经元中表达的核受体LXRs。该项目结合了体内和体内 体外方法：1）研究LXR直接激活以及受LXR调节的下游途径 感觉神经元中的脂质，2）确定LXR通路是否有助于II型糖尿病神经病变 在感觉神经元中，使用神经元特异性缺失小鼠模型和高脂饮食（HFD）诱导的 神经病变模型（cre-lox模型），3）确定LXR激动剂是否保护免受HFD诱导的神经病变 通过调节DRG小感觉神经元中的通路（RiboTag模型）。中央统一 假设PNS神经元中LXR的激活调节下游LXR依赖性程序， 在高脂营养面前维持正常的PNS功能。长期高脂饮食有望诱导 LXR信号改变导致PNS功能障碍。 这些研究将开始破译脂质感受器核的细胞、分子和生理作用。 受体在II型糖尿病小鼠模型的外周神经元中的表达。预计结果将告知未来 机制研究和药物开发，旨在解决未满足的临床治疗需求 肥胖引起的神经病变及其主要并发症II型糖尿病。

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.