Brain Immune Interactions In Type 2 Diabetes

描述(申请人提供)：2型糖尿病(DM)是美国第六大主要死亡原因。最近，2型糖尿病与亚急性慢性炎症有关，表现为糖尿病前期和非糖尿病患者的炎症细胞因子水平升高，如IL-1β、IL-6和肿瘤坏死因子(TNF)-α。此外，2型糖尿病患者糖皮质激素水平升高，表明下丘脑-垂体-肾上腺(HPA)轴激活。我们实验室的最新研究表明，BKS.Cg-m+/+Leprdb(db/db)2型糖尿病小鼠模型在疾病行为和天然免疫方面有明显的变化。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，与类似处理的杂合子对照(db/+)小鼠相比，这些小鼠对IL-1β更敏感，表现出更多的社会探索损失。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(IRSS)丝氨酸磷酸化，阻断细胞因子作用，以及高血糖依赖的蛋白激酶C(PKC)增量激活，负向调节先天免疫。因此，这项研究项目的目的是检验这一假说，即2型糖尿病导致应激障碍，从而增强大脑对促炎细胞因子的反应性。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。这些目标和目标将在以下四个具体目标中实现。在目标1中，我们将研究内毒素攻击db/db小鼠发热增加和社会探索丧失的生理学原因。在目标2中，我们将确定糖尿病前期的高胰岛素血症如何负面调节抗炎细胞因子IL-4的信号。在目标3中，我们将探讨高血糖增强天然免疫的机制。在目标4中，我们将使用一种药理学方法来降低db/db小鼠对发热和疾病行为的易感性。需要这些研究来了解糖尿病相关的慢性炎症是如何影响神经免疫系统的。

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.