Brain Immune Interactions In Type 2 Diabetes

在美国，2型糖尿病(DM)是第六大死亡原因。最近，2型糖尿病一直在 与亚急性慢性炎症有关，表现为炎症细胞因子水平升高，如白细胞介素2 糖尿病前期和非糖尿病患者的(IL)-I[3，IL-6和肿瘤坏死因子(TNF)-ct。此外，糖皮质激素 2型糖尿病患者血清白蛋白水平升高，提示下丘脑-垂体-肾上腺(HPA)轴激活。新的 我们实验室的研究表明，BKS.Cg-m+/+Leprdb(db/db)小鼠模型对2型糖尿病有明显的治疗作用 疾病行为和先天免疫力的改变。我们发现db/db小鼠对 脂多糖(LPS)表现出发烧增加，社交探索减少。我们还观察到， 这些小鼠对IL-1更敏感[3]，与类似的小鼠相比，表现出更多的社会探索损失 杂合子对照(db/+)小鼠。重要的是，我们已经确定了解释这些问题的潜在机制 异常现象。这些原因包括高胰岛素血症引起的胰岛素受体底物丝氨酸磷酸化。 (IRSS)负性阻断细胞因子作用和高血糖依赖性蛋白激酶C(PKC)8的激活 调节先天免疫。因此，本研究项目的目的是检验假设类型 2糖尿病导致应激障碍，增强大脑对促炎细胞因子的反应性。长期的 本项目的目标是了解2型糖尿病增强先天免疫的机制。 炎症和疾病行为。这些目标和目标将在以下四个具体方面实现 目标。在目标1中，我们将研究发烧增加和社会探索丧失的生理原因。 脂多糖刺激db/db小鼠。在目标2中，我们将确定糖尿病前期的高胰岛素血症是如何阴性的。 调节抗炎细胞因子IL-4的信号。在目标3中，我们将通过以下方式研究这一机制 高血糖可以增强先天免疫力。在目标4中，我们将使用药理学方法来减少 Db/db小鼠对发热和疾病行为的易感性。我们需要这些研究来了解 糖尿病相关的慢性炎症会影响神经免疫系统。 这是最初提交的申请1 R01 DK064862-01的修改后的提交 强调小组ZRG1 IFCN-2。

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)-I [3, IL-6 and tumor necrosis factor (TNF)-ct 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 to lipopolysaccharide (LPS) demonstrating increased fever and reduced social exploration. We also observed that these mice are more sensitive to IL-1 [3 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)8 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. This is a revised submission of application 1 R01 DK064862-01 that was originally Emphasis Panel ZRG1 IFCN-2.