A multi-disciplinary approach to the identification of host metabolic determinan

鉴定宿主代谢决定因素的多学科方法

• 批准号: 10089386
• 负责人: MEGAN B MURRAY
• 金额: $ 78.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089386
• 关键词: Affect; Body mass index; Cavia; Cell Maturation; Code; Data; Dendritic Cells; Dendritic cell activation; Disease; Future; Gene Expression Profiling; Genes; Genetic study; Household; Human; Immune; Immune response; Individual; Infection; Integration Host Factors; Interleukin-1; Intervention; Intervention Studies; Link; Metabolic; Metabolic Pathway; Metabolic syndrome; Microbiology; Minority; Molecular; Mycobacterium tuberculosis; Myeloid Cells; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Pathway interactions; Peruvian; Pharmacology; Population; Research Design; Risk; Risk Factors; Severity of illness; Testing; Therapeutic Intervention; Tuberculosis; Validation; Variant; Work; cohort; dietary; exome; experimental study; genetic variant; indexing; interdisciplinary approach; macrophage; porcine model; therapeutic development; trait

Although only a minority of individuals infected with Mycobacterium tuberculosis progress to active disease, host factors associated with progression are only poorly understood. Recent data show that metabolic risk factors such as low body-mass index, metabolic syndrome and type 2 diabetes mellitus are strong predictors of an individual's risk of progressing to active disease after infection. Further, growing evidence suggests a link between an individual's metabolic state and control of human macrophage and dendritic cell activation and differentiation pathways. Here, we propose to identify key host metabolic pathways involved in TB progression in a genetic study of an existing TB exposed cohort and then test these associations by performing observational studies in humans and intervention studies in guinea pig models. First, we will leverage our existing cohort of microbiologically confirmed TB index cases and their exposed, infected household contacts who have remained disease free for two years after exposure. Using a nested case control study design, we will assess the impact of genetic variants known to affect key metabolic traits as well as rare coding variants on TB progression using exome chips that are optimized for the Peruvian population in which we work. Second, we will use the results of this study to guide further validation of these determinants through transcriptional profiling of human myeloid cells from cases and exposed non-diseased controls. In a sub-study, we will also these exome chip and transcriptional profiling data to identify the genes involved in dendritic cell maturation as assessed by genes related to CD1, interleukin-1 and NFkappaB. To further explore the impact of these metabolic and immune pathways, we will conduct TB infection experiments in guinea pigs in which metabolic status is modified through dietary and pharmacological interventions with the aim of identifying possible therapeutic interventions that could moved to human trials in future work.

尽管只有少数感染结核分枝杆菌的个体会发展为活动性疾病， 对与进展相关的宿主因素知之甚少。最近的数据表明，代谢风险 低体重指数、代谢综合征和 2 型糖尿病等因素是强有力的预测因素 个人感染后进展为活动性疾病的风险。此外，越来越多的证据表明 个体的代谢状态与人类巨噬细胞和树突状细胞激活的控制之间的联系 和分化途径。在这里，我们建议确定结核病涉及的关键宿主代谢途径 在现有结核病暴露人群的基因研究中发现进展，然后通过以下方法测试这些关联： 在人类中进行观察性研究，并在豚鼠模型中进行干预研究。首先，我们将 利用我们现有的微生物学确诊的结核病指数病例及其暴露、感染病例队列 暴露后两年内未患病的家庭接触者。使用嵌套案例 对照研究设计，我们将评估已知影响关键代谢特征的遗传变异的影响，例如 以及使用针对秘鲁人优化的外显子组芯片的结核病进展的罕见编码变体 我们工作的人口。其次，我们将利用本研究的结果来指导这些研究的进一步验证。 通过对病例和未患病暴露的人类骨髓细胞进行转录分析来确定决定因素 控制。在一项子研究中，我们还将这些外显子组芯片和转录谱数据来识别基因 通过与 CD1、白介素-1 和 NFkappaB 相关的基因评估，参与树突状细胞成熟。到 进一步探讨这些代谢和免疫途径的影响，我们将进行结核感染 通过饮食和药物改变代谢状态的豚鼠实验 干预措施的目的是确定可能的治疗干预措施，这些干预措施可以转移到人体试验中 未来的工作。