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.

项目总结/摘要 在结核病也流行的国家，糖尿病患者的增加导致了结核病的重新出现。 糖尿病是结核病的一个严重危险因素。迫切需要实施结核病战略 预防和控制暴露于结核分枝杆菌（Mtb）的数百万糖尿病患者， 肺结核的病原体虽然糖尿病已知可以调节免疫反应，但大多数关于糖尿病的研究 TB-糖尿病合并症主要集中在淋巴细胞功能的改变上。肺 巨噬细胞是对Mtb应答的第一批宿主细胞之一， 细胞类型决定疾病的后果。我们以前的工作已经证明肺 巨噬细胞代谢在促进或控制TB的进展中起关键作用。但无论 糖尿病患者对结核病的易感性增加是由肺巨噬细胞代谢活动的改变引起的， 几乎不为人知，因此存在重大的知识差距。组织驻留基因的表型和功能 巨噬细胞在很大程度上受到其环境生态位中营养水平的影响。鉴于糖尿病 诱导慢性高血糖症，这是糖尿病条件下导致TB发展的关键因素，我们 假设由于高血糖环境导致肺巨噬细胞代谢改变， 增加了糖尿病患者对结核病的易感性。我们将用两个目标来检验这个假设：目标1。确定影响 高血糖对结核分枝杆菌感染时肺泡巨噬细胞代谢状态和容许性的影响。目标2. 探讨高血糖如何影响肺结核患者肺巨噬细胞的异质性。我们将使用多- 学科方法，包括代谢，基因组学和微生物学，以询问潜在的 从全新的角度研究结核病-糖尿病合并症的机制。