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，最了解的危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病比例的疾病综合体。由于很少有研究能够更好地理解结核病与DM之间的复杂相互作用，因此对基本疾病发病机理几乎没有什么了解。基于人类的流行病学和临床研究数量有限，我们知道与非糖尿病患者相比，DM患者的临床结局较差，并且死亡的风险更大。 TB和DM具有与过度氧化组织损伤有关的常见发病机理。我们建议的核心是在豚鼠（GPS）中使用实验性分枝杆菌（MTB）感染，它们会形成与天然结核病的人类相似的肺和肺外病变。在拟议的研究中，我们假设抗氧化能力的耗竭会导致氧化组织损害，两种疾病都共享这种基本疾病机制，并且在合并后，导致更严重且广泛传播的结核病，对常规抗菌治疗的反应较差。我们将使用胰岛素依赖性糖尿病（IDDM，I型）和非胰岛素依赖性糖尿病（NIDDM，type 2）的新型胰岛素依赖性糖尿病模型（IDDM，I型）和非高强度ERDMAN MTB的感染感染。我们将使用这些模型来探索基本的疾病发病机理，并测试可用于治疗人类的新型治疗策略。我们的初步数据表明，与正常血糖水平的GP相比，具有血糖水平升高的MTB感染的GPS具有更严重和广泛传播的TB病变，具有更高的细菌负担。此外，我们表明，仅MTB感染会诱导慢性高血糖状态，并且这种病可能加剧疾病并限制对治疗的反应。我们的目的是：（1）验证TB与GPS中IDDM和NIDDM结合的模型，（2）定义氧化应激的作用以及抗氧化剂防御剂在DM中GPS中TB的发病机理中的耗竭，（3）确定（3）确定抗氧化剂是否可以恢复抗氧化剂防御剂，以及（4）它们是否会增强使用IDDM和NIDDM在GPS中抗TB药物的有效性。通过更好地了解结核病与DM并发的发病机理，可以将新的治疗策略添加到控制人类结核病的全球斗争中，尤其是在患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，患有糖尿病的人患严重结核病（TB）的风险更高。由于未知原因，糖尿病和结核病都很难治疗。我们研究的目的是在患有糖尿病的豚鼠中开发一个结核病模型，该模型可用于测试两种疾病的新治疗策略。我们从用结核病治疗糖尿病豚鼠中学到的东西可以直接应用于人类疾病的组合，这一问题现在正在世界各地出现。