Brain Immune Interactions In Type 2 Diabetes

2 型糖尿病中的脑免疫相互作用

• 批准号: 7340452
• 负责人: Gregory G Freund
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340452
• 关键词: Accounting; Advanced Glycosylation End Products; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Brain; Caring; Cause of Death; Cells; Chronic; Cytokine Signaling; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Fever; Glucocorticoids; Goals; Heterozygote; Hyperglycemia; Hyperinsulinism; Immune; Immunosuppressive Agents; Inflammation; Inflammatory; Instinct; Insulin; Insulin Receptor; Insulin Resistance; Interleukin-1; Interleukin-1 beta; Interleukin-4; Interleukin-6; Interleukins; Laboratories; Link; Lipopolysaccharides; Mediating; Metabolic; Molecular; Mus; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Peritoneal Macrophages; Persons; Phosphorylation; Physiological; Predisposition; Prevalence; Principal Investigator; Protein Kinase C; Protein Tyrosine Phosphatase; Recovery; Reporting; Research; Research Project Grants; Resistance; Serine; Signal Transduction; Sirolimus; Skeletal Muscle; System; Traumatic Stress Disorders; Tumor Necrosis Factor-alpha; United States; brain behavior; citrate carrier; cost; cytokine; db/db mouse; diabetic; glucose uptake; human IRS2 protein; hypothalamic-pituitary-adrenal axis; improved; inhibitor/antagonist; innovation; insulin signaling; mimetics; mouse model; novel; phosphatase inhibitor; programs; protein kinase C-delta; receptor mediated endocytosis; research study; response; scavenger receptor; social; vanadyl sulfate

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.

描述（由申请人提供）：2 型糖尿病 (DM) 是美国第六大死因。最近，2 型糖尿病与亚急性慢性炎症有关，糖尿病前期和糖尿病患者体内炎症细胞因子如白细胞介素 (IL)-1β、IL-6 和肿瘤坏死因子 (TNF)-α 水平升高就表明了这一点。此外，2 型糖尿病中糖皮质激素水平升高，表明下丘脑-垂体-肾上腺 (HPA) 轴激活。我们实验室的新研究表明，2型糖尿病的BKS.Cg-m +/+ Leprdb (db/db)小鼠模型在疾病行为和先天免疫方面有显着的改变。我们发现 db/db 小鼠对脂多糖 (LPS) 具有高反应性，表现出发烧增加和社交探索减少。我们还观察到，与接受类似治疗的杂合子对照 (db/+) 小鼠相比，这些小鼠对 IL-1beta 更敏感，表现出社交探索能力的丧失增加。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，阻断细胞因子的作用，以及高血糖依赖性蛋白激酶 C (PKC)δ 激活，负向调节先天免疫。因此，本研究项目的目的是检验 2 型糖尿病会诱发应激障碍，从而增强大脑对促炎细胞因子的反应性这一假设。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。这些目的和目标将通过以下四个具体目标来实现。在目标 1 中，我们将检查 LPS 攻击的 db/db 小鼠发烧加剧和社交探索丧失的生理原因。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向调节抗炎细胞因子 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 小鼠对发烧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。