Phagosomal Ion Channels as Therapeutic Targets

吞噬体离子通道作为治疗靶点

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：单核吞噬细胞通过吞噬细胞的摄取和杀死细菌入侵者、清除凋亡细胞、抗原呈递和囊泡分泌之间的组合相互作用来协调先天免疫反应这些功能的核心是离子通道和转运蛋白的激活，这些离子通道和转运蛋白驱动细胞内区室的功能，以及质子转位 ATP 酶启动吞噬体区室以实现有效的杀菌活性。，以及用于动员和释放的分泌囊泡，吞噬体内 pH、Cl 含量和膜电位的动态变化对于最佳状态的发展至关重要。杀菌性吞噬体腔内离子含量变化的驱动力相对未知，并且可能是高度动态的。该提案将探讨吞噬体 pH 值与存在于其中的离子通道的身份、调节和激活之间的相互依赖性。吞噬体膜的活性和由此产生的吞噬体内容物的变化是吞噬体内抗菌环境的主要决定因素，因此，是新治疗靶点的主要候选者。我们将探索独特的调节信号转导途径来调节吞噬体中的离子通道运输/表达，以优化对摄入生物体的杀灭。本申请中提出的实验的目标是优化动态功能谱。监测巨噬细胞吞噬体的离子环境在形成和成熟过程中的变化，从机制上定义有助于该过程的分子成分。这些拟议的研究将解决单价和二价阳离子通量是否可以替代的问题。驱动杀菌活性的非功能性Cl-通道；如果是这样，我们将确定离子运动和转运元件的时空调节，从而微调和维持杀菌环境。总而言之，这些研究将为探索新机制提供方法论和模板，这些新机制可能以宿主导向的方式解决多种肺部疾病（包括结核病、慢性肺阻塞性疾病）中的炎症他们还将提供一个路线图，有助于研究各种细胞生物学环境和疾病状态下的其他细胞内细胞器。