Macrophage metabolism in diabetes and tuberculosis comorbidity

糖尿病和结核病合并症中的巨噬细胞代谢

• 批准号: 10645801
• 负责人: Lu Huang
• 金额: $ 24.47万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645801
• 关键词: ATAC-seq; Address; Agreement; Alveolar Macrophages; Biological Assay; Bone Marrow; Cell Energetics; Cells; Cholesterol; Chromatin; Chronic; Communicable Diseases; Consumption; Country; Cues; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Environment; Epigenetic Process; Exhibits; Exposure to; Fatty Acids; Gene Expression Profile; Genetic Transcription; Genomics; Genus Hippocampus; Glucose; Glycolysis; Growth; Heterogeneity; Hyperglycemia; Immune response; Impairment; In Vitro; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Link; Lung; Lymphocyte Function; Macrophage; Metabolic; Metabolic Diseases; Metabolism; Microbiology; Molecular; Mus; Mycobacterium tuberculosis; Nutrient; Pathogenesis; Pathogenicity; Pathway interactions; Patient risk; Patients; Phagocytosis; Phenotype; Play; Predisposition; Prevention; Public Health; Reporter; Reporting; Risk Factors; Role; Streptozocin; Testing; Therapeutic; Time; Tissues; Translational Repression; Transposase; Tuberculosis; Work; bacterial fitness; cell type; comorbidity; diabetic; diabetic patient; exposed human population; extracellular; fatty acid oxidation; glycemic control; immunoregulation; interdisciplinary approach; interstitial; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; pandemic disease; pathogen; permissiveness; pulmonary function; receptor; response; single-cell RNA sequencing; transcriptome sequencing; virtual

Project Summary/Abstract The increase in diabetes patients in countries where tuberculosis (TB) is also endemic has led to the re-emerging importance of diabetes as a serious risk factor for TB. There is an urgent need to implement strategies for TB prevention and control among the millions of diabetes patients exposed to Mycobacterium tuberculosis (Mtb), the causative agent of TB. Although diabetes is known to modulate immune responses, most of the studies on TB-diabetes comorbidity have been primarily focused on the altered functions of lymphocytes. Lung macrophages are among the first host cells that respond to Mtb and are recognized as one of the most crucial cell types in determining the consequences of disease. Our previous work has demonstrated that lung macrophage metabolism plays a critical role in promoting or controlling the progression of TB. However, whether the increased susceptibility to TB in diabetes is caused by altered metabolic activities in lung macrophages is virtually unknown, thus representing a significant knowledge gap. The phenotype and functions of tissue-resident macrophages are greatly influenced by the level of nutrients in their environmental niches. Given that diabetes induces chronic hyperglycemia, a key factor that contributes to the development of TB in diabetic conditions, we hypothesize that the altered metabolism in lung macrophages, due to the hyperglycemic environment, leads to increased susceptibility to TB in diabetes. We will test this hypothesis with two aims: Aim 1. Determine the impact of hyperglycemia on the metabolic status and permissiveness of lung AMs during Mtb infection. Aim 2. Interrogate how hyperglycemia influences the heterogeneity of lung macrophages in TB. We will use multi- disciplinary approaches, including metabolism, genomics and microbiology to interrogate the underlying mechanism of TB-diabetes comorbidity from a completely novel perspective.

项目摘要/摘要 结核病（TB）也流行的国家的糖尿病患者增加导致重新出现 糖尿病是结核病的严重危险因素的重要性。迫切需要为结核病实施策略 暴露于结核分枝杆菌（MTB）的数百万糖尿病患者中的预防和控制 结核病的病因。尽管已知糖尿病可以调节免疫反应，但大多数研究 结核病合并症主要集中在淋巴细胞的改变功能上。肺 巨噬细胞是对MTB响应的第一个宿主细胞之一，被认为是最关键的宿主细胞之一 确定疾病后果的细胞类型。我们以前的工作证明了肺 巨噬细胞代谢在促进或控制结核病进展方面起关键作用。但是，是否 糖尿病中结核病的易感性提高是由肺巨噬细胞中代谢活性改变引起的 几乎未知，因此代表了一个重要的知识差距。组织居民的表型和功能 巨噬细胞受到环境壁ches中养分水平的极大影响。鉴于糖尿病 诱导慢性高血糖，这是有助于糖尿病状况中结核病发展的关键因素，我们 假设由于高血糖环境而导致的肺巨噬细胞中的代谢改变导致 增加了糖尿病中结核病的敏感性。我们将以两个目的检验这一假设：目标1。确定影响 MTB感染期间肺AMS的代谢状况和允许性高血糖。目标2。 询问高血糖如何影响结核病中肺巨噬细胞的异质性。我们将使用多 纪律方法，包括新陈代谢，基因组学和微生物学来询问潜在的 从完全新颖的角度来看，结核病糖尿病的机理合并症。