Elucidating the link between Mycobacterium tuberculosis potassium homeostasis and its lipid metabolism and growth in vivo
阐明结核分枝杆菌钾稳态与其脂质代谢和体内生长之间的联系
基本信息
- 批准号:10509286
- 负责人:
- 金额:$ 24.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-25 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectArchitectureBacteriaBiologyC3HeB/FeJ MouseCarbonChloridesCholesterolComplementComprehensionCuesDataDevelopmentEnsureEnvironmentEnvironmental ImpactEquilibriumFoamy MacrophageFoundationsGenetic TranscriptionGoalsGrowthHeterogeneityHomeostasisHumanIndividualInfectionLesionLightLinkLipidsMaintenanceMetabolismMethodologyMicroscopyModelingMusMycobacterium tuberculosisNecrotic LesionNutrientPathway interactionsPhysiologyPotassiumReporterReportingResolutionRoleSS DNA BPSignal TransductionSourceStructureSystemTestingTherapeuticTissuesTracerTuberculosisVariantenvironmental disparityexperienceexperimental studyextracellularhost colonizationin vivoinnovationinsightlipid metabolismmutantnoveloverexpressionresponsesuccesstranscription factortranscriptome sequencinguptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Successful host colonization by Mycobacterium tuberculosis (Mtb) requires that the bacteria sense and
respond to disparate environmental cues coordinately during infection, and adapt its physiology accordingly.
This includes an ability to respond to acidic pH and maintain intrabacterial ionic homeostasis, as well as
utilization of lipid carbon sources during infection. However, how Mtb ionic cue response and homeostasis and
its lipid metabolism are functionally connected remains poorly understood. Intriguingly, we have found that Mtb
lipid metabolism and its potassium (K+) response/homeostasis is linked. For example, the bacterial response to
cholesterol is repressed upon disruption of intrabacterial K+ homeostasis, and growth in cholesterol media of a
Mtb mutant disrupted in K+ homeostasis is impeded at pH 7, but not pH 6. Aim 1 of this proposal thus seeks to
define the global impact of Mtb K+ homeostasis disruption on the bacterium’s ability to utilize cholesterol,
examining both transcriptional response and utilizing a fluorescent cholesterol tracer for the analysis of
cholesterol uptake. Aim 2 focuses on understanding the functional impact of local environmental differences on
intrabacterial K+ homeostasis and Mtb replication status during infection, with single bacterium resolution. It will
exploit the use of a novel fluorescent reporter that reports on intrabacterial K+ levels, with tests on wild type
Mtb and mutants in several key lipid utilization regulators. Single bacterium level analysis in vivo is particularly
critical due to the marked heterogeneity in both local pH and nutrient sources experienced by Mtb during
infection, which extends to non-uniformity spatially within canonical caseous necrotic lesions. As such, Aim 2
studies will further exploit combination of a fluorescent replication reporter with a Mtb mutant disrupted for
intrabacterial K+ homeostasis, in a murine infection model that recapitulates highly structured caseous necrotic
lesions observed during human infection. These in vivo experiments will enable elucidation of how differences
in local environment (pH, carbon source etc.) during infection may alter the relative need for active
maintenance of intrabacterial K+ homeostasis by Mtb for replication success. This project is conceptually
innovative in examining how Mtb K+ homeostasis affects its lipid metabolism in a pH-dependent manner, an
intersection of vital aspects of Mtb infection biology that is unexplored. There is further methodological
innovation in the development of a new intrabacterial [K+] reporter to delineate the impact of local environment
in vivo on Mtb K+ homeostasis. These studies will provide the foundation for understanding the concept of an
intrinsic link between Mtb metabolism and ionic cue response and homeostasis, a facet of Mtb infection biology
that holds the potential for exploitation for therapeutic purposes.
项目总结/摘要
结核分枝杆菌(Mtb)的成功宿主定殖需要细菌感测和
在感染过程中协调地对不同的环境线索做出反应,并相应地调整其生理机能。
这包括响应酸性pH和维持细菌内离子稳态的能力,以及
在感染期间利用脂质碳源。然而,如何结核杆菌离子线索的反应和稳态,
其脂质代谢在功能上的联系仍然知之甚少。有趣的是,我们发现结核分枝杆菌
脂质代谢和其钾(K+)反应/体内平衡是相关联的。例如,细菌对
胆固醇在细菌内K+稳态破坏时受到抑制,
Mtb突变体在K+稳态中被破坏,在pH 7下受到阻碍,但在pH 6下不受阻碍。因此,本提案的目标1力求
确定结核分枝杆菌K+稳态破坏对细菌利用胆固醇的能力的全球影响,
检查转录反应并利用荧光胆固醇示踪剂分析
胆固醇摄取目标2侧重于了解当地环境差异对
感染期间细菌内K+稳态和Mtb复制状态,单个细菌分辨率。它将
利用一种新的荧光报告基因,报告细菌内K+水平,并对野生型进行测试
几种关键脂质利用调节因子的结核分枝杆菌及其突变体。体内单个细菌水平分析特别适用于
关键是由于在当地的pH值和营养来源的显着异质性经历的结核分枝杆菌在
感染,其在典型干酪样坏死病变内扩展到空间上的不均匀性。因此,Aim 2
研究将进一步开发荧光复制报告基因与被破坏的Mtb突变体的组合,
在小鼠感染模型中再现高度结构化干酪性坏死的细菌内K+稳态
在人类感染期间观察到的病变。这些体内实验将能够阐明差异如何
在当地环境中(pH、碳源等)在感染期间可能会改变对活性物质的相对需求,
通过Mtb维持细菌内K+稳态以获得复制成功。这个项目在概念上
在研究结核分枝杆菌K+稳态如何以pH依赖性方式影响其脂质代谢方面具有创新性,
Mtb感染生物学重要方面的交叉点尚未探索。还有一种方法
创新开发了一种新的细菌内[K+]报告基因,以描述局部环境的影响
体内对Mtb K+稳态的影响。这些研究将为理解一个概念的基础,
结核分枝杆菌代谢与离子提示反应和稳态之间内在联系,结核分枝杆菌感染生物学的一个方面
有可能被用于治疗目的。
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 }}
Shumin Tan其他文献
Shumin Tan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('Shumin Tan', 18)}}的其他基金
Elucidating the link between Mycobacterium tuberculosis potassium homeostasis and its lipid metabolism and growth in vivo
阐明结核分枝杆菌钾稳态与其脂质代谢和体内生长之间的联系
- 批准号:
10628034 - 财政年份:2022
- 资助金额:
$ 24.75万 - 项目类别:
Unraveling the link between serine/threonine protein kinase and two-component system regulation of environment-mediated Mycobacterium tuberculosis growth arrest
揭示丝氨酸/苏氨酸蛋白激酶与环境介导的结核分枝杆菌生长停滞的双组分系统调节之间的联系
- 批准号:
10428709 - 财政年份:2022
- 资助金额:
$ 24.75万 - 项目类别:
Unraveling the link between serine/threonine protein kinase and two-component system regulation of environment-mediated Mycobacterium tuberculosis growth arrest
揭示丝氨酸/苏氨酸蛋白激酶与环境介导的结核分枝杆菌生长停滞的双组分系统调节之间的联系
- 批准号:
10693160 - 财政年份:2022
- 资助金额:
$ 24.75万 - 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
- 批准号:
10468026 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
- 批准号:
10684689 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
- 批准号:
10020314 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
- 批准号:
10225474 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Bacterial Sensing and Response to Chloride as a Novel Tuberculosis Drug Target
细菌对氯化物作为新型结核病药物靶点的感知和反应
- 批准号:
9304978 - 财政年份:2016
- 资助金额:
$ 24.75万 - 项目类别:
Bacterial Sensing and Response to Chloride as a Novel Tuberculosis Drug Target
细菌对氯化物作为新型结核病药物靶点的感知和反应
- 批准号:
8966959 - 财政年份:2015
- 资助金额:
$ 24.75万 - 项目类别:
相似海外基金
CAREER: Efficient Algorithms for Modern Computer Architecture
职业:现代计算机架构的高效算法
- 批准号:
2339310 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Continuing Grant
Hardware-aware Network Architecture Search under ML Training workloads
ML 训练工作负载下的硬件感知网络架构搜索
- 批准号:
2904511 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Studentship
CAREER: Creating Tough, Sustainable Materials Using Fracture Size-Effects and Architecture
职业:利用断裂尺寸效应和架构创造坚韧、可持续的材料
- 批准号:
2339197 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant
Travel: Student Travel Support for the 51st International Symposium on Computer Architecture (ISCA)
旅行:第 51 届计算机体系结构国际研讨会 (ISCA) 的学生旅行支持
- 批准号:
2409279 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant
Understanding Architecture Hierarchy of Polymer Networks to Control Mechanical Responses
了解聚合物网络的架构层次结构以控制机械响应
- 批准号:
2419386 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant
I-Corps: Highly Scalable Differential Power Processing Architecture
I-Corps:高度可扩展的差分电源处理架构
- 批准号:
2348571 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant
Collaborative Research: Merging Human Creativity with Computational Intelligence for the Design of Next Generation Responsive Architecture
协作研究:将人类创造力与计算智能相结合,设计下一代响应式架构
- 批准号:
2329759 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant
The architecture and evolution of host control in a microbial symbiosis
微生物共生中宿主控制的结构和进化
- 批准号:
BB/X014657/1 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Research Grant
RACCTURK: Rock-cut Architecture and Christian Communities in Turkey, from Antiquity to 1923
RACCTURK:土耳其的岩石建筑和基督教社区,从古代到 1923 年
- 批准号:
EP/Y028120/1 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Fellowship
NSF Convergence Accelerator Track M: Bio-Inspired Surface Design for High Performance Mechanical Tracking Solar Collection Skins in Architecture
NSF Convergence Accelerator Track M:建筑中高性能机械跟踪太阳能收集表皮的仿生表面设计
- 批准号:
2344424 - 财政年份:2024
- 资助金额:
$ 24.75万 - 项目类别:
Standard Grant