Therapeutic Restoration of Metabolic Homeostasis During Active TB

活动性结核病期间代谢稳态的治疗性恢复

• 批准号: 8773050
• 负责人: Randall J Basaraba
• 金额: $ 22.31万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773050
• 关键词: 1,2-diacylglycerol; Address; Adipose tissue; Animal Model; Antibiotic Therapy; Antibiotics; Antitubercular Agents; Bacterial Infections; Blood Glucose; Carrier Proteins; Cavia; Chronic; Clinical Research; Combination Drug Therapy; Communicable Diseases; Data; Diabetes Mellitus; Diglycerides; Disease; Disease Progression; Drug usage; Dyslipidemias; Effectiveness; Euglycemic Clamping; FDA approved; Glucose; Glucose Clamp; Glucose Transporter; Homeostasis; Human; Hyperglycemia; Immune response; Infection; Insulin; Insulin Receptor; Insulin Resistance; Laboratories; Lead; Length; Lesion; Link; Lipids; Liver; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Mycobacterium tuberculosis; Nonesterified Fatty Acids; Pancreatic Hormones; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Predisposition; Protein Kinase C; Receptor Signaling; Research; Risk; Second Messenger Systems; Serum; Severity of illness; Skeletal Muscle; Techniques; Testing; Therapeutic; Time; Tissues; Tuberculosis; antimicrobial; antimicrobial drug; base; blood glucose regulation; diabetic; fatty acid metabolism; glucose metabolism; impaired glucose tolerance; improved; in vivo; innovation; insulin sensitivity; lipid metabolism; non-diabetic; public health relevance; response; restoration; second messenger; therapy design; treatment response; tuberculosis drugs; tuberculosis treatment; wasting

DESCRIPTION (provided by applicant): It is estimated that more than a third of the world's human population (over 2 billion people) are infected with Mycobacterium tuberculosis (Mtb). One of the major hurdles to controlling the global spread of TB is the length of time required to effectively treat patients with active TB disease. It has been known for decades that humans infected with Mtb develop profound alterations in systemic glucose metabolism reflected by elevated blood glucose levels (hyperglycemia) and impaired glucose tolerance, which is restored to normal only after months of antimicrobial drug therapy. Moreover, TB patients also develop elevated serum free fatty acid levels (FFAs), which in a variety of non-TB diseases have been shown to be potent mediators of systemic insulin resistance. Since 1) altered fatty acid metabolism is directly linked to dysregulated glucose homeostasis and 2) systemic insulin resistance is the most common cause of impaired glucose tolerance, we will test the hypothesis that: Impaired glucose tolerance during Mtb infection is due to insulin resistance and that therapeutic restoration of systemic glucose homeostasis will slow TB disease progression and improve antimicrobial drug treatment responses. In these studies we will not only determine the molecular pathogenesis of altered glucose metabolism associated with active Mtb infection but also determine whether restoring metabolic homeostasis with antiglycemic drugs is beneficial as an adjunct to antimicrobial therapy. Our preliminary data show that, like humans, Mtb infected guinea pigs develop impaired glucose tolerance and elevated serum FFAs and that hyperglycemia exacerbates TB disease severity. In non-TB diseases like diabetes, it is well accepted that hyperglycemia is due to impaired glucose tolerance resulting from decreased sensitivity of certain tissues (skeletal muscle, liver and adipose tissue) to the activity of the pancreatic hormone insulin, which is referred to as insulin resistance. Based on these concepts we will use the guinea pig TB model to determine the molecular mechanisms of impaired glucose tolerance and whether restoring glucose homeostasis therapeutically alone or in combination with antimicrobial drugs, improves host responses to Mtb infection. In Aim 1, we will determine whether impaired glucose tolerance and the resulting hyperglycemia is due to systemic insulin resistance mediated by the subcellular distribution and accumulation of the lipid second messenger diacylglycerol (DAG). In Aim 2, we will determine whether restoring and maintaining systemic glucose homeostasis with FDA approved, antiglycemic drugs will slow TB disease progression in Mtb-infected guinea pigs. We will also determine whether the use of antiglycemic drugs, when combined with antimicrobial drugs, improves TB treatment responses. Collectively, these studies will determine whether the altered glucose metabolism observed during Mtb infection contributes to TB pathogenesis and if therapeutic restoration of metabolic homeostasis improves antimicrobial drug treatment responses. These studies address an urgent, unmet need for innovative strategies to improve current TB drug treatments.

描述（由申请人提供）：据估计，超过三分之一的人口（超过20亿人）感染了结核分枝杆菌（MTB）。控制结核病全球扩散的主要障碍之一是有效治疗活性结核病患者所需的时间。数十年来，感染了MTB的人会在血糖水平升高（高血糖）和葡萄糖耐受性损害反映的全身性葡萄糖代谢中产生深刻的改变，仅在几个月后，葡萄糖耐受性就恢复到正常情况。此外，结核病患者还会发展出升高的血清无脂肪酸水平（FFA），在多种非TB疾病中，已证明它们是全身性胰岛素抵抗的有效介质。由于1）脂肪酸代谢改变与葡萄糖稳态失调直接相关，并且2）全身性胰岛素抵抗是导致葡萄糖耐受性受损的最常见原因，我们将检验以下假说：受影响的葡萄糖耐受性在MTB感染过程中，MTB感染的疾病耐药性和疾病的恢复会加剧。抗菌药物治疗反应。在这些研究中，我们不仅将确定与活性MTB感染相关的葡萄糖代谢改变的分子发病机制，而且还确定是否恢复了用抗血糖药物恢复代谢稳态作为抗菌治疗的辅助性。我们的初步数据表明，像人类一样，MTB感染的豚鼠会产生葡萄糖耐受性受损和血清FFA升高，并且高血糖症加剧了TB疾病的严重程度。在糖尿病等非TB疾病中，高血糖症是由于某些组织（骨骼肌，肝脏和脂肪组织）对胰腺激素胰岛素的活性的敏感性（骨骼肌，肝脏和脂肪组织）的敏感性降低而导致的葡萄糖耐受性受损众所周知。基于这些概念，我们将使用豚鼠TB模型来确定葡萄糖耐受性受损的分子机制，以及是否单独恢复葡萄糖稳态，还是与抗菌药物结合使用，改善了宿主对MTB感染的反应。在AIM 1中，我们将确定葡萄糖耐受性受损和产生的高血糖是否是由于全身性胰岛素抵抗引起的，该抗细胞分布和脂质第二质体二酰二酰基甘油（DAG）的积累介导。在AIM 2中，我们将确定使用经FDA批准的恢复和维持全身性葡萄糖稳态，抗血糖药物会减慢MTB感染的豚鼠的结核病进展。我们还将确定在与抗菌药物结合使用时，使用抗血糖药物是否会改善结核病治疗反应。总的来说，这些研究将确定MTB感染期间观察到的葡萄糖代谢改变是否有助于TB发病机理以及代谢稳态的治疗恢复是否可以改善抗菌药物治疗反应。这些研究涉及对改善当前结核病药物治疗的创新策略的紧急，未满足的需求。