Impact of Diabetes and Hyperlipidemia on Host Defense

糖尿病和高脂血症对宿主防御的影响

• 批准号: 7568987
• 负责人: Hardy Kornfeld
• 金额: $ 39.45万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568987
• 关键词: 1,2-diacylglycerol; Accounting; Acute; Advanced Glycosylation End Products; Aerosols; Angiotensin II; Animal Model; Apolipoprotein E; Attention; Automobile Driving; Basic Science; Biochemical; Biochemical Pathway; Biological Markers; Blood Pressure; Cell physiology; Cholesterol; Chronic; Clinical; Complications of Diabetes Mellitus; Data; Dendritic Cells; Diabetes Mellitus; Diabetic mouse; Diet; Diglycerides; Dose; Drug Design; Dyslipidemias; Fatty acid glycerol esters; Growth; Hexosamines; Histopathology; Host Defense; Human; Hyperglycemia; Hyperlipidemia; Immune; Immune system; Immunity; Impairment; Infection; Inflammation; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knock-out; Knockout Mice; Knowledge; Learning; Leukocytes; Link; Lung; Metabolism; Modeling; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmaceutical Preparations; Predisposition; Production; Protein Kinase C; Pyridoxamine; Resistance; Role; Serum; Signal Transduction; Streptozocin; Sucrose; T-Lymphocyte; Testing; Time; Tuberculosis; Vascular Diseases; Virulent; adiponectin; aminoguanidine; base; benphothiamine; cytokine; diabetic; fighting; high standard; hypercholesterolemia; inhibitor/antagonist; insight; macrophage; mortality; non-diabetic; novel; oxidized low density lipoprotein; polyol; prevent; protective efficacy; research study; response; therapy development; tuberculosis drugs; type I and type II diabetes

Increased susceptibility to infections including tuberculosis (TB) is a major cause of morbidity and mortality in diabetes. Despite its clinical importance, this phenomenon has received little basic research attention. We will investigate TB resistance in mice using models of type 1 and type 2 diabetes. Diabetic and non-diabetic control mice will be challenged by low-dose aerosol infection with Mycobacterium tuberculosis (Mtb). We will characterize TB susceptibility with parameters of survival, bacterial load, and lung leukocyte recruitment. The basis of susceptibility will be evaluated by characterizing cytokine expression and by testing macrophage, dendritic cell, and T cell functions. We will investigate whether advanced glycation end products (AGE), which have been linked to diverse complications of diabetes, are responsible for impaired host defense. We will also evaluate the potential role of other biochemical mechanisms implicated in diabetes complications including polyol pathway flux, hexosamine pathway flux, and over-production of diacylglycerol with activation of protein kinase C. Hyperlipidemia is a common co-morbidity in diabetes that exacerbates diabetic vasculopathy. In preliminary studies we found that hypercholesterolemia also increases TB susceptibility. We will explore similarities and differences in the effects of diabetes and hyperlipidemia on protective immunity, and we will characterize TB susceptibility of mice with combined hyperlipidemia and diabetes. This project will identify specific deficits in protective immunity caused by hyperglycemia and hyperlipidemia, and may provide new insights to critical parameters of host defense against TB. Understanding the mechanisms of susceptibility will inform the development of treatments to reverse this diabetes-related complication. At the same time our model will be used to test the impact on protective immunity of novel treatments for diabetes co-morbidities such as statins, aminoguanidine and pyridoxamine. While our focus is on TB, the new knowledge generated by this project will have broad relevance to other infections associated with diabetes and will further basic understanding of the interplay between immunity and metabolism. This project studies how diabetes weakens the body's ability to fight tuberculosis. Learning more about the harmful effects of diabetes on the immune system will suggest new ways to prevent and treat infections that are a major problem in people with diabetes.

提高了包括结核病（TB）在内的感染的敏感性是导致发病率和死亡率的主要原因 糖尿病。尽管具有临床意义，但这种现象几乎没有受到基础研究的关注。我们 将使用1型和2型糖尿病模型研究小鼠的结核病耐药性。糖尿病和非糖尿病 对照小鼠将受到结核分枝杆菌（MTB）的低剂量气溶胶感染的挑战。我们将 用生存，细菌负荷和肺白细胞募集的参数来表征结核病敏感性。这 易感性的基础将通过表征细胞因子表达和测试巨噬细胞来评估 树突状细胞和T细胞功能。我们将调查高级糖基化末端产品（年龄）， 与糖尿病的多种并发症有关的，导致宿主防御受损。我们 还将评估与糖尿病并发症有关的其他生化机制的潜在作用 包括多元通路通量，己糖胺途径通量和激活过度生产二酰基甘油 蛋白激酶C.高脂血症是糖尿病中常见的合并症，加剧了糖尿病 血管病。在初步研究中，我们发现高胆固醇血症也会增加结核病的敏感性。我们 将探索糖尿病和高脂血症对保护性免疫的影响的相似性和差异， 我们将表征与高脂血症和糖尿病联合血症小鼠的结核病敏感性。这个项目 将确定由高血糖和高脂血症引起的保护性免疫的特定缺陷，并且可能 为针对结核病的主机防御的关键参数提供新的见解。了解机制 易感性将为逆转与糖尿病有关的并发症的疗法开发。在 同时，我们的模型将用于测试对糖尿病新型治疗方法的保护性免疫的影响 他汀类药物，氨基瓜胺和吡啶胺等合并症。虽然我们的重点是结核病 该项目产生的知识将与与糖尿病相关的其他感染具有广泛的相关性 并将进一步了解免疫与代谢之间的相互作用。 该项目研究糖尿病如何削弱人体对抗结核病的能力。了解更多有关 糖尿病对免疫系统的有害影响将提出预防和治疗感染的新方法 是糖尿病患者的主要问题。