Impact of Diabetes and Hyperlipidemia on Host Defense

描述(申请人提供)：对包括结核病(TB)在内的感染的易感性增加是糖尿病发病率和死亡率的主要原因。尽管它在临床上很重要，但这种现象很少受到基础研究的关注。我们将使用1型和2型糖尿病模型来研究小鼠对结核病的耐药性。糖尿病和非糖尿病对照组小鼠将受到低剂量气雾剂感染结核分枝杆菌(Mtb)的挑战。我们将通过存活率、细菌负荷和肺白细胞募集等参数来表征结核病的易感性。敏感性的基础将通过表征细胞因子的表达和检测巨噬细胞、树突状细胞和T细胞功能来评估。我们将调查与糖尿病的各种并发症有关的晚期糖基化终末产物(AGE)是否与宿主防御受损有关。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，包括多元醇途径通量、己糖胺途径通量和蛋白激酶C激活的二酰甘油过量生产。高脂血症是糖尿病常见的并存疾病，可加剧糖尿病血管病变。在初步研究中，我们发现高胆固醇血症也会增加结核病的易感性。我们将探索糖尿病和高脂血症对保护性免疫的影响的异同，并将研究高脂血症和糖尿病合并的小鼠对结核病的易感性。该项目将确定高血糖和高脂血症引起的保护性免疫的特定缺陷，并可能为宿主防御结核病的关键参数提供新的见解。了解易感性的机制将有助于开发逆转这种糖尿病相关并发症的治疗方法。同时，我们的模型将被用来测试治疗糖尿病合并疾病的新疗法，如他汀类药物、氨基胍和吡哆胺对保护性免疫的影响。虽然我们的重点是结核病，但该项目产生的新知识将与其他与糖尿病相关的感染具有广泛的相关性，并将进一步加深对免疫和新陈代谢之间相互作用的基本理解。该项目研究糖尿病如何削弱人体抗击结核病的能力。更多地了解糖尿病对免疫系统的有害影响，将为预防和治疗感染提供新的方法，感染是糖尿病患者的主要问题。

DESCRIPTION (provided by applicant): 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.