Brain Immune Interactions In Type 2 Diabetes

描述（由申请人提供）：2型糖尿病（DM）是美国第六大死亡原因。最近，2型糖尿病与亚急性慢性炎症有关，如在糖尿病前期和明显糖尿病患者中升高的炎性细胞因子如白细胞介素（IL）-1 β、IL-6和肿瘤坏死因子（TNF）-α。此外，糖皮质激素水平增加2型糖尿病表明激活下丘脑-垂体-肾上腺（HPA）轴。本实验室的最新研究表明，BKS.Cg-m +/+ Leprdb（db/db）型2型糖尿病小鼠模型在疾病行为和先天免疫方面有明显的改变。我们发现db/db小鼠对脂多糖（LPS）具有高反应性，表现出发热增加和社会探索减少。我们还观察到，这些小鼠对IL-1 β更敏感，与类似处理的杂合子对照（db/+）小鼠相比，表现出社会探索的丧失增加。重要的是，我们已经确定了解释这些异常的潜在机制。这些原因包括高胰岛素血症诱导的胰岛素受体底物（IRS）丝氨酸磷酸化阻断细胞因子作用和高血糖依赖性蛋白激酶C（PKC）δ激活负调节先天免疫。因此，本研究项目的目的是检验2型糖尿病诱导应激障碍，增强大脑对促炎细胞因子的反应性的假设。该项目的长期目标是了解2型糖尿病增强先天免疫，炎症和疾病行为的机制。这些宗旨和目标将在以下四个具体目标中实现。在目标1中，我们将检查LPS攻击db/db小鼠中发热增加和社会探索丧失的生理原因。在目标2中，我们将确定糖尿病前期高胰岛素血症如何负调节抗炎细胞因子IL-4的信号传导。在目标3中，我们将研究高血糖增强先天免疫的机制。在目标4中，我们将使用药理学方法来降低db/db小鼠对发热和疾病行为增加的易感性。需要这些研究来了解糖尿病相关的慢性炎症如何影响神经免疫系统。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (DM) is the sixth leading cause of death in the United States. Recently type 2 DM has been linked to subacute chronic inflammation as shown by elevated levels of inflammatory cytokines like interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha in persons with pre- and frank diabetes. In addition, glucocorticoid levels are increased in type 2 DM indicating activation of the hypothalamic-pituitary-adrenal (HPA) axis. New research from our laboratory shows that the BKS.Cg-m +/+ Leprdb (db/db) mouse model of type 2 DM has marked alterations in sickness behavior and innate immunity. We found that db/db mice are hyper-responsiveness [sic] to lipopolysaccharide (LPS) demonstrating increased fever and reduced social exploration. We also observed that these mice are more sensitive to IL-1beta showing increased loss of social exploration when compared to similarly treated heterozygote control (db/+) mice. Importantly, we have identified potential mechanisms to account for these abnormalities. These causes include hyperinsulinemia-induced serine phosphorylation of insulin receptor substrates (IRSs) blocking cytokine action and hyperglycemia-dependent protein kinase C (PKC)delta activation negatively regulating innate immunity. Therefore, the objective of this research project is to examine the hypothesis that type 2 DM induces a stress disorder that enhances brain responsivity to pro-inflammatory cytokines. The long-term goal of this project is to understand the mechanism by which type 2 DM augments innate immunity, inflammation and sickness behavior. These objectives and goals will be pursued in the following four Specific Aims. In Objective 1, we will examine the physiologic cause of increased fever and loss of social exploration in LPS-challenged db/db mice. In Objective 2, we will determine how hyperinsulinemia in pre-diabetes negatively regulates signaling of the anti-inflammatory cytokine IL-4. In Objective 3, we will investigate the mechanism by which hyperglycemia augments innate immunity. In Objective 4, we will use a pharmacologic approach to reduce susceptibility to increased fever and sickness behavior in db/db mice. These studies are needed to understand how diabetes-associated chronic inflammation affects the neuroimmune system.