Phagosomal Ion Channels as Therapeutic Targets

吞噬体离子通道作为治疗靶点

• 批准号: 9213389
• 负责人: DEBORAH J. NELSON
• 金额: $ 49.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-09 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213389
• 关键词: Address; Alveolar; Alveolar Macrophages; Animal Disease Models; Antibiotics; Antigen Presentation; Apoptosis; Apoptotic; Asthma; Automobile Driving; Bacteria; Bacterial Infections; Biological; Biological Assay; Carrier Proteins; Cations; Cell membrane; Cell physiology; Cells; Cellular biology; Charge; Chloride Channels; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Communicable Diseases; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Diagnostic; Disease; Divalent Cations; Drug Targeting; Elements; Engineering; Environment; Event; G-substrate; GTP-Binding Protein alpha Subunits, Gs; Goals; Homeostasis; Human; Immune; Infection; Infectious Lung Disorder; Inflammation; Ingestion; Innate Immune Response; Invaded; Investigation; Ion Channel; Ion Transport; Ions; Knowledge; Lung; Lung diseases; Mediating; Membrane; Membrane Potentials; Methodology; Microbial Drug Resistance; Molecular; Monitor; Mononuclear; Monovalent Cations; Movement; Organelles; Organism; Pathology; Pathway interactions; Phagocytes; Phagosomes; Pharmacology; Population; Process; Protein translocation; Proteome; Proton-Translocating ATPases; Recruitment Activity; Regulation; Reporting; Resistance development; Resolution; Sampling; Secretory Vesicles; Sentinel; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Time; Tuberculosis; Vesicle; antimicrobial; bactericide; combat; combinatorial; convict; design; driving force; experimental study; fighting; granulocyte; improved; killings; macrophage; microbial; microbicide; mutant; new therapeutic target; novel; pathogen; protein function; protein transport; public health relevance; receptor; response; roscovitine; screening; shunt pathway; small molecule; spatiotemporal; therapeutic target; tool; trafficking; uptake; vacuolar H+-ATPase

 DESCRIPTION (provided by applicant): Mononuclear phagocytes orchestrate the innate immune response through the combinatorial interplay between the phagocytic uptake and killing of bacterial invaders, clearance of apoptotic cells, antigen presentation, and secretion of vesicle bound signaling molecules to recruit help in the clearance of infection. Central to each of these functions is the activation of ion channels and transporter proteins that drive function in intracellular compartments. Chloride channels as well as proton translocating ATPases prime the phagosomal compartment for effective bactericidal activity, and secretory vesicles for mobilization and release. Dynamic changes in intraphagosomal pH, Cl- content, and membrane potential are essential to the development of an optimal bactericidal phagosomal lumen. The driving force for changes in ionic content in the small intraphagosomal volume is relatively unknown and likely to be highly dynamic. This proposal will explore the interdependence of phagosomal pH and the identity, regulation, and activation of ion channels present in the phagosomal membrane. Ion channel activity and the resultant changes in phagosomal content are prime determinants of the antimicrobial milieu within the phagosome and, therefore, are prime candidates for new therapeutic targets. We will explore unique regulatory signal transduction pathways to modulate ion channel trafficking/expressing in the phagosome to optimize killing of ingested organisms. The goal of the experiments proposed in this application is the optimization of dynamic functional profiles for monitoring changes in the ionic milieu of th macrophage phagosome during formation and maturation, defining mechanistically the molecular components contributing to the process. These proposed studies will address the question of whether monovalent and divalent cation flux can replace non-functional Cl- channels in driving bactericidal activity; and if so, how the appropriate channels can be recruited to the phagosome. We will determine the spatiotemporal regulation of the ionic movements and the transporter elements which can fine tune and maintain the microbicidal environment. In toto, these studies will provide both methodology and a template for the exploration of novel mechanisms which might resolve inflammation in a host-directed manner in a diversity of pulmonary diseases including tuberculosis, chronic pulmonary obstructive disease (COPD), cystic fibrosis (CF) and asthma. They also will provide a roadmap that could be helpful for the study of other intracellular organelles in a wide range of cell biological contexts and disease states.

 描述（由适用提供）：单核吞噬细胞通过吞噬摄取和杀死细菌入侵者的吞噬剂之间的组合相互作用来协调先天的免疫响应 结合信号分子以募集感染的帮助。这些功能中的每一个的中心是驱动在细胞内隔室中功能的离子通道和转运蛋白的激活。氯化物通道以及质子易位ATPases为有效杀菌活性的吞噬体室和用于动员和释放的秘密蔬菜。吞噬体内pH，CL-含量和膜电位的动态变化对于开发最佳细菌吞噬体腔是必不可少的。小吞咽体体积中离子含量变化的驱动力相对尚不清楚，并且可能是高度动态的。该建议将探讨吞噬体pH的相互依赖性以及吞噬膜中存在的离子通道的身份，调控和激活。离子通道活性和吞噬体含量的最终变化是吞噬体内抗菌环境的主要决定者，因此是新治疗靶标的主要候选者。我们将探索独特的调节信号传输途径，以调节吞噬体中的离子通道运输/表达以优化摄入生物的杀死。在本应用中提出的实验的目的是优化动态功能曲线，以监视形成和成熟过程中巨噬细胞吞噬体离子环境变化的变化，从而在机械上定义了有助于该过程的分子成分。这些提出的研究将解决一个问题，即单价和二价阳离子通量是否可以替代驱动细菌活性的非功能性CL通道。如果是这样，可以将适当的渠道招募到吞噬体。我们将确定可以对微生物环境微调和维持微生物环境的离子运动和转运蛋白元件的空间时间调节。在TOTO中，这些研究将提供方法和模板，以探索新型机制，这些机制可能会以宿主指导的方式以多种肺部疾病来解决炎症，包括结核病，慢性肺阻塞性疾病（COPD），囊性纤维化（CF）和哮喘。他们还将提供一个路线图，这可能有助于研究在各种细胞生物学环境和疾病状态下其他细胞内细胞器。