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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要在结核病 (TB) 也流行的国家，糖尿病患者的增加导致结核病重新出现糖尿病作为结核病严重危险因素的重要性。迫切需要实施结核病战略预防和控制数百万暴露于结核分枝杆菌（Mtb）的糖尿病患者，结核病的病原体。尽管已知糖尿病会调节免疫反应，但大多数研究都是关于结核病-糖尿病合并症主要集中在淋巴细胞功能的改变上。肺巨噬细胞是最早对 Mtb 做出反应的宿主细胞之一，被认为是最重要的宿主细胞之一。细胞类型决定疾病的后果。我们之前的工作表明，肺巨噬细胞代谢在促进或控制结核病进展中发挥着关键作用。然而，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改变引起的几乎不为人知，因此存在巨大的知识差距。组织驻留的表型和功能巨噬细胞很大程度上受环境中营养物质水平的影响。鉴于糖尿病诱发慢性高血糖，这是导致糖尿病患者发生结核病的一个关键因素，我们假设由于高血糖环境，肺巨噬细胞代谢的改变导致糖尿病患者对结核病的易感性增加。我们将通过两个目标来检验这一假设：目标 1. 确定影响 Mtb 感染期间高血糖对肺 AMs 代谢状态和许可性的影响。目标2。探讨高血糖如何影响结核病中肺巨噬细胞的异质性。我们将使用多学科方法，包括新陈代谢、基因组学和微生物学，以探究潜在的问题从全新的角度研究结核病-糖尿病合并症的机制。