Lung-Protective Mechanisms of Metformin in TB
二甲双胍治疗结核病的肺保护机制
基本信息
- 批准号:10556391
- 负责人:
- 金额:$ 63.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-05 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAccelerationAdultAerosolsAlveolarAntigensBloodCD44 geneCD8B1 geneCXCL10 geneCXCR3 geneCell Differentiation processCellsCirculationClinicalClinical TrialsCollagenDataDevelopmentDiabetes MellitusDiseaseDown-RegulationDrug resistanceElementsEpigenetic ProcessFibrosisFrequenciesGene ExpressionGene Expression RegulationGoalsHumanITGAM geneImmuneImmunityImpairmentIndividualInfectionInfiltrationInflammationInjuryKnowledgeLigandsLungMacrophageMaintenanceMediatingMemoryMetforminModelingMoralityMusMycobacterium tuberculosisMyelogenousNOTCH1 geneNatural ImmunityNon-Insulin-Dependent Diabetes MellitusOutcomeParticipantPathologyPathway interactionsPatientsPeripheral Blood Mononuclear CellPersonsPhagocytesPharmaceutical PreparationsPlasmaProteomicsPulmonary FibrosisPulmonary TuberculosisRNARecurrenceRegimenReportingResolutionRiskSELL geneSamplingSignal TransductionSpecificitySpleenSputumSterilizationStructure of parenchyma of lungSurvivorsT memory cellT-LymphocyteTestingTherapy trialToxic effectTrainingTreatment EfficacyTuberculosisUp-Regulationadenylate kinaseantifibrotic treatmentantimicrobialdesignexperimental studyfibrogenesisfightingglobal healthimprovedindium-bleomycinlung injurylung preservationmonocytemortalitymouse modelnew therapeutic targetnovelnovel strategiespulmonary functionrecruitresponsesmall moleculetissue repairtranscriptome sequencingtranscriptomicstuberculosis immunitytuberculosis treatmentvalidation studiesvirtual
项目摘要
PROJECT SUMMARY
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat.
Challenges of compliance and toxicities of prolonged antimicrobial regimens and increasing drug resistance
highlight the need for novel treatment approaches. Host-directed therapy (HDT) harnesses host-intrinsic
mechanisms using small molecule drugs to accelerate sterilization and limit lung damage caused by host
immunity. We reported that metformin reduced lung bacterial load and immune pathology in Mtb-infected
mice. Retrospective data from over half a million individuals treated for diabetes with metformin support the
HDT potential of this drug. These studies reported lower rates of Mtb infection and progression from latent to
active TB, less cavitation and all-cause mortality, accelerated sputum conversion and less TB recurrence.
The goal of this project is to discern the mechanisms of metformin HDT efficacy, focusing on inflammation
and fibrosis. Our preliminary data suggest that metformin expands non-classical Ly6Clo monocytes in an
AMPK-dependent manner. These cells are essential for host protection in innate “trained” immunity and they
participate in tissue repair. Ly6Clo monocytes produce CXCL10 that recruits CD8+CXCR3+ memory (TM) cells,
which may restrict Mtb replication in an antigen-specific and non-specific manner. Our data also suggest that
metformin-mediated protection involves NOTCH pathway modulation, with suppression of NOTCH1 that
drives fibrosis and enhancement of NOTCH2 to regulates Ly6Clo monocyte and CD8+ TM cell differentiation.
Experiments in Aim 1 will establish the requirement for AMPK and NOTCH signaling in the protective
functions of metformin using the mouse aerosol TB model. Outcomes are lung bacterial load, immune
pathology, lung tissue damage with collagen remodeling and transcriptomic and proteomic markers of
fibrogenesis. Immunometabolic and epigenetic regulatory activities of metformin will be investigated in the
context of TB-HDT. Experiments in Aim 2 will establish the requirements for CD8+ TM cells and the CXCL10-
CXCR3 axis in host protection and evaluate potential similarities and differences between metformin-
educated CD8+ TM cells and virtual memory T cells. Both Aims include validation studies using alternative
mouse models (C3HeB/FeJ and Collaborative Cross) and de-identified human plasma, blood RNA and
PBMC samples from clinical TB studies having participants with or without metformin exposure. This project
will produce new knowledge about the mechanisms of metformin TB-HDT efficacy that will support the design
and interpretation of human clinical trials using metformin and might identify new targets for HDT agents
having greater specificity, efficacy and tolerability than metformin.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Hardy Kornfeld其他文献
Hardy Kornfeld的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Hardy Kornfeld', 18)}}的其他基金
BSL3 Enhancements for RNA Virus Pandemic Preparedness
BSL3 针对 RNA 病毒大流行防范的增强
- 批准号:
10611745 - 财政年份:2022
- 资助金额:
$ 63.76万 - 项目类别:
Lung-Protective Mechanisms of Metformin in TB
二甲双胍治疗结核病的肺保护机制
- 批准号:
10338184 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Sirtuins and Host Metabolism in TB Pathogenesis and Treatment
Sirtuins 和宿主代谢在结核病发病机制和治疗中的作用
- 批准号:
10208211 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Sirtuins and Host Metabolism in TB Pathogenesis and Treatment
Sirtuins 和宿主代谢在结核病发病机制和治疗中的作用
- 批准号:
10620121 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Sirtuins and Host Metabolism in TB Pathogenesis and Treatment
Sirtuins 和宿主代谢在结核病发病机制和治疗中的作用
- 批准号:
10390487 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Trial of Metformin for TB/HIV Host-directed Therapy
二甲双胍用于结核病/艾滋病毒宿主定向治疗的试验
- 批准号:
10644973 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Trial of Metformin for TB/HIV Host-directed Therapy
二甲双胍用于结核病/艾滋病毒宿主定向治疗的试验
- 批准号:
9926218 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Planning for the Metformin for TB/HIV Host-directed Therapy (METHOD) Trial
规划二甲双胍用于结核病/艾滋病毒宿主定向治疗 (METHOD) 试验
- 批准号:
9138531 - 财政年份:2016
- 资助金额:
$ 63.76万 - 项目类别:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 63.76万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 63.76万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 63.76万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 63.76万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 63.76万 - 项目类别:
Studentship Programs














{{item.name}}会员




