Linking Receptor-Mediated Phagocytosis and cAMP Pathways in Macrophage Responses to Tuberculosis

将受体介导的吞噬作用和 cAMP 通路与巨噬细胞对结核病的反应联系起来

• 批准号: 10369686
• 负责人: Chrissy Leopold Wager
• 金额: $ 7.92万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369686
• 关键词: Adenosine Monophosphate; Adipocytes; Agonist; Alveolar Macrophages; Area; Attenuated; Biomedical Research; C-Type Lectins; Cause of Death; Cells; Communicable Diseases; Communication; Complement; Conflict (Psychology); Containment; Core Facility; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Data Analyses; Development; Disease; Educational process of instructing; Environment; Equilibrium; Fellowship; Gene Expression; Gene Proteins; Goals; Growth; Human; Hydrolysis; Immune response; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory Response; Invaded; Investigation; Journals; Knock-in Mouse; Laboratories; Lead; Learning; Ligation; Link; Literature; Lung; Macrophage Activation; Measures; Mediating; Mentors; Metabolic; Modeling; Mus; Mycobacterium tuberculosis; Nuclear Receptors; PPAR gamma; Pathogenesis; Pathway interactions; Periodicity; Persons; Phagocytosis; Play; Production; Proteins; Pulmonary alveolar structure; Regulation; Research; Research Institute; Research Training; Resolution; Resources; Role; Route; Scientist; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Study models; Techniques; Testing; Texas; Time; Training; Tuberculosis; Virulent; Work; antagonist; arm; career; career development; eicosanoid metabolism; global health; humanized mouse; immunoregulation; improved; in vivo; in vivo Model; inhibitor; innovation; knock-down; macrophage; mannose receptor; monocyte; mouse model; novel; novel strategies; novel therapeutic intervention; pathogen; pathogenic bacteria; phosphoric diester hydrolase; programs; protein expression; receptor; receptor expression; response; skills; trafficking; transcription factor; translational model; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB) and the leading cause of death from a single infectious agent. An estimated 10 million people developed TB disease in 2017, demonstrating an urgent need to new therapeutic approaches, including host-directed therapy (HDT) to halt infection and progression of active TB. Macrophages often serve as the first line of defense against invading pathogens. However, M.tb modulates macrophage cell signaling pathways to induce an environment beneficial to its intracellular survival. The strategies employed by M.tb are an active area of investigation. The overall goal of the laboratory is to identify intracellular master regulators of inflammation and metabolic intermediates that dictate human macrophage responses to M.tb. Previous work in our lab revealed that M.tb interaction with the macrophage mannose receptor (MR) activates peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that dampens the inflammatory response and is associated with increased M.tb growth. The proposed research plan will investigate the hypothesis that MR ligation by M.tb initiates the cAMP signaling pathway leading to PPARγ activation, resulting in enhanced survival of M.tb in macrophages. The Specific Aims are to: 1) Determine the role of phosphodiesterases (PDEs) in regulating PPARγ activity through the cAMP signaling pathway during M.tb infection of hMDMs, 2) Determine the role of Protein Kinase A (PKA) and Exchange Protein Directly Activated by cAMP 1 (Epac1) in regulating PPARγ activity following M.tb-elicited cAMP production in hMDMs, and 3) Determine the effects of MR/cAMP/PKA/Epac1/PPARγ signaling on M.tb pathogenesis. The proposed project will further elucidate the signaling pathway(s) downstream of MR ligation by M.tb, an area only minimally investigated. In addition, this project uses an innovative, newly developed humanized mouse model to study human MR in vivo devoid of the murine MR which is a confounding factor to data analysis. Investigation of the cAMP pathway is expected to identify new, druggable host cell targets for HDT against TB. This research plan affords me the ability to learn new scientific techniques, new models to study infectious diseases, detailed data analysis and the training to shape the direction of this project and my career. The training plan outlines career development activities including opportunities to improve my scientific presentation and communication skills, grantsmanship, mentoring and teaching skills. The research and training will take place at the Texas Biomedical Research Institute with a deep commitment to scientific training, evidenced by numerous journal clubs, seminars and full support of the Texas Biomed Association for Trainees. Texas Biomed has various core facilities, high containment research labs for M.tb work both in vitro and in mice and NHPs, and all resources needed for excellent scientific training. At fellowship completion, I will be prepared to lead a research program in host/pathogen interaction as an independent scientist.

项目摘要/摘要 结核分枝杆菌（M.TB）是结核病的病因（TB），是死亡的主要原因 来自一个传染剂。估计有1000万人在2017年出现结核病疾病，表明 迫切需要采用新的治疗方法，包括宿主指导的治疗（HDT），以阻止感染和 活性结核的进展。巨噬细胞通常是针对入侵病原体的第一道防线。 但是，M.TB调节巨噬细胞信号传导途径，以诱导有益的环境 细胞内存活。 M.TB采用的策略是积极的投资领域。总体目标 该实验室是要确定炎症和代谢中间的细胞内主调节剂， 决定人类巨噬细胞对M.TB的反应我们实验室的先前工作表明，M.TB与 巨噬细胞甘露糖受体（MR）激活过氧化物组增殖物激活的受体伽马（PPARγ），A 转录因子会跳动炎症反应，并与M.TB生长增加有关。这 拟议的研究计划将调查以下假设：M.TB的结扎先生启动营地信号传导 导致PPARγ激活的途径，导致巨噬细胞中M.TB的存活增强。具体目标 为：1）确定磷酸二酯酶（PDE）在通过CAMP确定PPARγ活性中的作用 M.TB感染HMDMS期间的信号传导途径，2）确定蛋白激酶A（PKA）和 在M.TB引诱后，在调节PPARγ活性中，CAMP 1（EPAC1）直接激活的交换蛋白质直接激活 HMDMS营地生产和3）确定MR/CAMP/PKA/EPAC1/PPARγ信号对M.TB的影响 发病。拟议的项目将进一步阐明MR连接下游的信号通路 由M.TB，仅对研究的区域进行了最小的研究。此外，该项目使用了创新的，新开发的 人源化小鼠模型研究人类MR没有鼠MR，这是一个混乱的因素 数据分析。对营地通路的调查有望确定HDT的新的，可吸毒的宿主细胞目标 反对结核病。该研究计划使我能够学习新的科学技术，新模型学习 传染病，详细的数据分析以及塑造该项目和我职业的方向的培训。 培训计划概述了职业发展活动，包括改善我的科学的机会 演示和沟通技巧，授予技巧，心理和教学技巧。研究和培训 将在得克萨斯州生物医学研究所举行，对科学培训的深刻承诺， 得克萨斯州生物管理学员协会的众多期刊俱乐部，半小伙子和全力支持证明了这一点。 德克萨斯州BioMed具有各种核心设施，用于M.TB的高容器研究实验室在体外和小鼠中工作 和NHP，以及出色的科学培训所需的所有资源。完成奖学金，我会做好准备 作为独立科学家，领导宿主/病原体相互作用的研究计划。