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Tuberculosis in diabetic guinea pigs

糖尿病豚鼠的结核病

基本信息

批准号：
8231331
负责人：
Randall J Basaraba
金额：
$ 22.05万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231331
关键词：
Activities of Daily Living Antioxidants Antitubercular Agents Attention Blood Glucose Cavia Cells Chronic Clinical Clinical Research Comorbidity Complex Country Data Defect Developing Countries Diabetes Mellitus Disease Effectiveness Environmental Risk Factor Epidemic Epidemiologic Studies Generations Goals Granuloma Host resistance Human Hyperglycemia Immune Infection Insulin-Dependent Diabetes Mellitus Lead Learning Lesion Life Style Literature Lung Mediating Metabolic Diseases Modeling Molecular Mycobacterium tuberculosis Necrosis Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidants Oxidative Stress Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Predisposition Reactive Oxygen Species Research Risk Risk Factors Rodent Role Severities Severity of illness Sputum Staining method Stains Testing Time Tissues Tuberculosis United States Virulent antimicrobial antimicrobial drug antioxidant therapy base burden of illness diabetic fighting high risk human disease non-diabetic novel novel therapeutics public health relevance response treatment strategy tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): One of the most serious and least understood risk factors for tuberculosis (TB) is diabetes mellitus (DM), a disease complex that is reaching epidemic proportions in many parts of the world. Because there have been few studies conducted to better understand the complex interactions between TB and DM, very little is known about the basic disease pathogenesis. Based on the limited number of epidemiological and clinical studies in humans, we know that patients with DM have poorer clinical outcomes and are at greater risk of dying compared to non-diabetic patients with TB. TB and DM share a common pathogenesis related to excessive oxidative tissue damage. Central to our proposal is the use of experimental Mycobacterium tuberculosis (Mtb) infections in guinea pigs (GPs), which develop pulmonary and extra-pulmonary lesions similar to humans with naturally occurring TB. In the proposed research we hypothesize that depletion of antioxidant capacity leads to oxidative tissue damage, that this basic disease mechanism is shared by both diseases, and, when combined, lead to more severe and widely disseminated TB with a poor response to conventional antimicrobial therapy. We will test this hypothesis with novel models of insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type 2) concurrent with infection by the highly virulent Erdman KO1 stain of Mtb. We will use these models to explore basic disease pathogenesis and to test novel therapeutic strategies that can be used to treat humans. Our preliminary data show that Mtb-infected GPs with elevated blood glucose levels developed more severe and widely disseminated TB lesions with a higher bacterial burden compared on GPs with normal blood glucose levels. In addition we show that Mtb infection alone induces a state of chronic hyperglycemia and that this condition may exacerbate disease and limit response to therapy. Our aims are to: (1) validate the models of TB combined with IDDM and NIDDM in GPs, (2) define the role of oxidative stress and the depletion of antioxidant defenses in the pathogenesis of TB in GPs with DM, (3) determine whether antioxidant drugs can restore antioxidant defenses, and (4) whether they will enhance the effectiveness of anti- TB drugs in GPs with IDDM and NIDDM. By better understanding the pathogenesis of TB concurrent with DM, new treatment strategies can be added to the global fight to control human tuberculosis especially in patients with these known risk factors. PUBLIC HEALTH RELEVANCE: Humans with diabetes are at higher risk of developing severe tuberculosis (TB) compared to non- diabetics. For unknown reasons, both diabetes and TB are difficult to treat when they occur together. The goal of our research is to develop a model of TB in guinea pigs with diabetes that can be used to test new treatment strategies for both diseases. What we learn from treating diabetic guinea pigs with TB can be directly applied to the human disease combination, a problem which is now emerging around the world.

描述（由申请人提供）：结核病（TB）最严重和最不了解的风险因素之一是糖尿病（DM），这是一种在世界许多地区达到流行比例的疾病。由于很少有研究更好地了解结核病和糖尿病之间的复杂相互作用，对基本疾病的发病机制知之甚少。基于有限数量的人类流行病学和临床研究，我们知道，与非糖尿病结核病患者相比，糖尿病患者的临床结局较差，死亡风险更大。结核病和糖尿病有一个共同的发病机制，涉及过度氧化组织损伤。我们的建议的核心是使用实验性结核分枝杆菌（Mtb）感染豚鼠（GP），其发展肺和肺外病变类似于人类自然发生的结核病。在拟议的研究中，我们假设抗氧化能力的耗尽导致氧化性组织损伤，这两种疾病共享这种基本的疾病机制，并且当结合时，导致更严重和广泛传播的结核病，对传统的抗菌治疗反应较差。我们将用胰岛素依赖型糖尿病（I型）和非胰岛素依赖型糖尿病（NIDDM，2型）并发高毒力Erdman KO 1株Mtb感染的新模型来检验这一假设。我们将使用这些模型来探索基本的疾病发病机制，并测试可用于治疗人类的新的治疗策略。我们的初步数据显示，与血糖水平正常的GP相比，血糖水平升高的结核分枝杆菌感染的GP发展出更严重和广泛播散的结核病病变，细菌负荷更高。此外，我们表明，结核分枝杆菌感染单独诱导慢性高血糖症的状态，这种情况下可能会加剧疾病和限制对治疗的反应。我们的目标是：（1）验证GP中TB合并IDDM和NIDDM的模型，（2）确定氧化应激和抗氧化防御的耗竭在GP合并DM的TB发病机制中的作用，（3）确定抗氧化药物是否可以恢复抗氧化防御，和（4）它们是否将增强抗TB药物在GP合并IDDM和NIDDM中的有效性。通过更好地了解结核病并发糖尿病的发病机制，新的治疗策略可以加入到全球控制人类结核病的斗争中，特别是在具有这些已知危险因素的患者中。公共卫生相关性：与非糖尿病患者相比，糖尿病患者患严重结核病（TB）的风险更高。由于未知的原因，糖尿病和结核病同时发生时很难治疗。我们研究的目标是在患有糖尿病的豚鼠中开发一种结核病模型，可用于测试这两种疾病的新治疗策略。我们从治疗患有结核病的糖尿病豚鼠中学到的知识可以直接应用于人类疾病组合，这是一个现在正在世界各地出现的问题。