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: 8645686
• 负责人: Hardy Kornfeld
• 金额: $ 40.3万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645686
• 关键词: 1,2-diacylglycerol; AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Advanced Glycosylation End Products; Aerosols; Africa; Alveolar Macrophages; Antigens; Apolipoprotein E; Apoptotic; Attention; Bacillus (bacterium); Biochemical; Biochemical Pathway; Cell Death; Cells; Cessation of life; China; Cholesterol; Chronic; Clinical Research; Complement; Complication; Complications of Diabetes Mellitus; Data; Dendritic Cells; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diglycerides; Disease; Dyslipidemias; Experimental Diabetes Mellitus; Foundations; Functional disorder; Funding; Future; Germ; Glucose; Glucosephosphate Dehydrogenase; Glyburide; Goals; Host Defense; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; In Vitro; India; Infection; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Invaded; Kidney; Knockout Mice; Knowledge; Leukocytes; Low Density Lipoprotein Receptor; Lung; M cell; Mediating; Metabolic Diseases; Methods; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathology; Pathway interactions; Population; Preclinical Testing; Predisposition; Prevention; Protein Isoforms; Protein Kinase C; Proteins; Public Health; Pyruvaldehyde; Receptor Activation; Recruitment Activity; Relative Risks; Retinal; Risk; Risk Factors; Scientist; Sentinel; Serum; Severities; Signal Transduction; Site; Streptozocin; Structure of lymph node of thorax; Testing; Triglycerides; Tuberculosis; Vaccination; Work; adaptive immunity; antimicrobial; base; cell mediated immune response; chemokine; chemotherapy; clinically relevant; clinically significant; cytokine; design; diabetic; glycation; hypercholesterolemia; immunopathology; improved; in vivo; inhibitor/antagonist; insight; killings; lipid metabolism; macrophage; mouse model; nerve injury; non-diabetic; pathogen; prevent; public health relevance; research study; response; time use; trafficking; type I and type II diabetes; vaccination against tuberculosis

DESCRIPTION (provided by applicant): We are studying the basis for increased tuberculosis (TB) susceptibility in diabetes mellitus (DM). The global population-attributable TB risk conferred by DM equals that of HIV/AIDS. Immune deficiency in DM is less severe than AIDS, but DM is more prevalent and is increasing sharply in India and China, which already have high rates of TB. In the first 3+ years of this project we discovered that mice with chronic hyperglycemia are more susceptible to TB than controls with higher bacillary burden and worse lung pathology. Diabetic mice with TB mount an exuberant Th1 biased cell mediated immune response with no evident gaps in leukocyte recruitment or expression of cytokines critical for TB defense. A key discovery was that the adaptive immune response to Mycobacterium tuberculosis (Mtb) is delayed in diabetic mice during the period of logarithmic bacillary replication. Diabetic mice are slow to develop aggregates of myeloid cells around Mtb-infected alveolar macrophages (AMF) and slow to deliver bacilli to the thoracic lymph nodes (TLN) where immunity is primed. Our data suggest the hypothesis that DM impairs a critical early step in TB defense where dendritic cells (DC) are recruited to foci of infected AMF to acquire bacilli and bring them to the TLN to initiate the adaptive response. We plan to test that hypothesis and to investigate its immunological and biochemical basis. Pilot data indicate that chemokines which signal DC recruitment are expressed in lower levels in diabetic than control mice early in TB. We will study DC trafficking in vivo and test the sentinel function of AMF in vivo and in vitro, as well as the impact of DM on AMF activation and cell death. Most human diabetics with TB have type 2 diabetes (T2D), whereas we have so far modeled insulin-deficient type 1 diabetes (T1D). We will therefore test TB susceptibility in mouse models of T2D. Most diabetic complications are mediated by chronic hyperglycemia and are shared by T1D and T2D, so we anticipate finding more similarities than differences in these models. Some diabetic complications are exacerbated by dyslipidemia. We discovered that hypercholesterolemia independently impairs TB defense. We now plan testing whether combined high glucose and high cholesterol or triglyceride synergistically weaken TB defense. Or studies so far used naove diabetic mice but humans may acquire latent TB infection before developing DM, which then raises the risk of developing active TB disease. Latency is not readily modeled in mice, but relevant data can be derived from proposed studies testing the impact of DM on the secondary response to Mtb in clinically relevant models of BCG vaccination and antimicrobial therapy. Finally, we will investigate the biochemical basis of diabetic TB susceptibility by testing effect of insulin or experimental DM complication therapies to restore TB defense. Diabetes is the most significant acquired risk factor for TB outside of Africa. Despite its significance this subject has received little attention from basic scientists. We are addressing a major gap in knowledge about a topic of growing public health importance and at the same time using our models to investigate fundamental issues in TB defense. PUBLIC HEALTH RELEVANCE: Tuberculosis kills two million people every year and one third of the world's population is infected with the germ that causes this disease. Diabetes increases the risk that people carrying the tuberculosis germ will develop tuberculosis disease and people with diabetes are more likely to have severe disease and a worse response to treatment. The goal of this project is to find the reason increased tuberculosis susceptibility in diabetes so that better methods to prevent or treat this complication can be designed.

描述（由申请人提供）：我们正在研究糖尿病（DM）中结核病（TB）易感性增加的基础。 DM赋予的全球人口 - 可替代的结核病风险等于艾滋病毒/艾滋病的风险。 DM的免疫缺陷比AIDS不那么严重，但是DM更为普遍，在印度和中国的TB率很高。在该项目的前3年中，我们发现患有慢性高血糖的小鼠比具有更高的细菌负担和较差的肺病理学的对照更容易受到结核病的影响。糖尿病小鼠带有结核病的糖尿病小鼠繁殖的Th1偏置细胞介导的免疫反应，在白细胞募集中没有明显的间隙或对结核防御至关重要的细胞因子的表达。一个关键的发现是，在对数细菌复制期间，糖尿病小鼠对结核分枝杆菌（MTB）的适应性免疫反应延迟。糖尿病小鼠在MTB感染的肺泡巨噬细胞（AMF）周围发展骨髓细胞的聚集体缓慢，并缓慢地向胸腔淋巴结（TLN）输送芽孢杆菌。我们的数据表明，DM会损害结核病防御的关键早期步骤，其中将树突状细胞（DC）招募到受感染AMF的焦点以获取杆菌并将其带到TLN以启动自适应反应。我们计划检验该假设并研究其免疫学和生化基础。试验数据表明，在糖尿病患者中，趋化因子在糖尿病中比对照小鼠在结核病早期以低水平表达。我们将在体内研究DC运输，并测试AMF在体内和体外的前哨功能，以及DM对AMF激活和细胞死亡的影响。大多数具有TB的人类糖尿​​病患者具有2型糖尿病（T2D），而到目前为止，我们已经建模了缺乏胰岛素的1型糖尿病（T1D）。因此，我们将在T2D的小鼠模型中测试TB敏感性。大多数糖尿病并发症是由慢性高血糖介导的，并由T1D和T2D共享，因此我们预计在这些模型中，发现比差异更多的相似之处。血脂异常加剧了一些糖尿病并发症。我们发现高胆固醇血症会独立损害结核病的防御。现在，我们计划测试高葡萄糖和高胆固醇或甘油三酸酯合并的结合，从而协同削弱了结核病防御。或迄今为止的研究使用了NAOVE糖尿病小鼠，但人类在发展DM之前可能会获得潜在的结核病感染，从而增加了患有活性结核病的风险。潜伏期不容易在小鼠中建模，但是可以从提出的研究中得出相关数据，该研究测试了DM对MTB的影响MTB在BCG疫苗接种和抗菌治疗的临床相关模型中的影响。最后，我们将通过测试胰岛素或实验性DM并发症疗法以恢复结核病防御的作用来研究糖尿病结核病易感性的生化基础。糖尿病是非洲以外的结核病最重要的危险因素。尽管有重要意义，但该主题很少受到基础科学家的关注。我们正在解决有关公共健康重要性日益严重的主题的主要差距，同时使用我们的模型来研究结核病防御中的基本问题。 公共卫生相关性：肺结核每年杀死200万人，世界三分之一的人口感染了引起这种疾病的细菌。糖尿病增加了携带结核病细菌的人会发性结核病的风险，糖尿病患者更有可能患有严重疾病，对治疗的反应较差。该项目的目的是找到增加糖尿病结核病敏感性的原因，以便可以设计出更好的预防或治疗这种并发症的方法。