Mitochondrial Calcium Signaling in Cell Intrinsic Immunity

细胞内在免疫中的线粒体钙信号传导

基本信息

批准号：
10620267
负责人：
BIMAL N. DESAI
金额：
$ 56.07万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2021-06-08 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620267
关键词：
3-Dimensional Address Apoptotic Architecture Basic Science Binding Biogenesis Bone Marrow Calcium Signaling Candida albicans Cells Citrates Citric Acid Cycle Clinical Complex Data Defense Mechanisms Detection EF Hand Motifs Exhibits Foundations Gatekeeping Gene Expression Goals Human Hybrids Immune response Immune system Immunity Immunologics Infection Inflammatory Inner mitochondrial membrane Ion Channel Lipids Macromolecular Complexes Macrophage Mediating Mediator Metabolic Metabolic stress Metabolism Mitochondria Mitochondrial Matrix Molecular Molecular Machines Molecular Target Monitor Movement Mus Mutation Myeloid Cells NADP NADPH Oxidase Neuromuscular Diseases Organelles Output Pathogen detection Pathogenicity Pathway interactions Phagocytes Phagocytosis Phagosomes Pharmaceutical Preparations Phase Physiology Play Process Production Public Health Publishing Regulation Reporting Research Resources Rest Role Sensory Receptors Sentinel Signal Transduction Small Interfering RNA Testing Ubiquitination antimicrobial calcium uniporter design electron tomography fascinate fighting immunomodulatory therapies immunoregulation in vivo innovation interest light microscopy microbial mitochondrial membrane mitochondrial metabolism novel pathogen pathogenic fungus pathogenic microbe pre-clinical programs pyruvate dehydrogenase reconstruction recruit response stoichiometry synaptic pruning tool transmission process vacuolar H+-ATPase

项目摘要

PROJECT SUMMARY The phagocytes of the immune system require a rapid burst of energy to phagocytose and kill pathogens in a timely manner. Energy demanding macromolecular complexes such as vacuolar ATPase (V-ATPase) and NADPH oxidase (NOX) complexes are recruited to the phagosome to acidify, oxidize, kill, and digest the pathogenic cargo. Reprogramming of the metabolic machinery by gene expression is too slow to meet the sharply increased demand for energy and metabolites. How do the sentinel phagocytes transmit the recognition of pathogens to switch the primary gears of cellular metabolism so rapidly? Our preliminary data indicated that the Ca2+-selective, mitochondrial ion channel, MCU, plays a crucial role in the signaling circuits that rapidly connect the sensory receptors of pathogens to the metabolic outputs necessary for phagosomal killing. Pursuing these tantalizing leads has now laid a strong scientific foundation to hypothesize that assembly of phagosome-mitochondria proximity architecture (PMPA) and mitochondrial Ca2+-signaling fuels cell-intrinsic immunity. In Aim1, we define the mechanisms underlying mitochondria-phagosome interactions triggered by C. albicans. In Aim 2, we define mechanisms through which mCa2+-signaling is regulated in activated macrophages. In Aim 3, we define the key metabolic outputs of mCa2+-signaling that drive microbial killing. This research is conceptually innovative because it unravels fascinating new connections between pathogen mitochondrial physiology, immunometabolism and microbial killing. Innovations include tools to monitor mCa2+-elevations in primary macrophages executing phagocytosis and Electron Tomography based 3D reconstructions of Mitochondria-Phagosome interactions. The research has the potential to reveal design principles that are of salience to other specialized phagocytic processes such as clearance of apoptotic cells, toxic debris, and synaptic pruning. From a translational/preclinical perspective, our findings may reveal novel molecular targets and pathways for new immunomodulatory therapies.

项目概要免疫系统的吞噬细胞需要快速爆发的能量才能及时吞噬并杀死病原体方式。需要能量的大分子复合物，例如液泡 ATP 酶（V-ATP 酶）和 NADPH 氧化酶（NOX）复合物被招募到吞噬体以酸化、氧化、杀死和消化致病物质。通过基因表达对代谢机制进行重新编程的速度太慢，无法满足急剧增加的需求用于能量和代谢物。前哨吞噬细胞如何传递对病原体的识别来切换细胞新陈代谢的主要齿轮如此迅速？我们的初步数据表明 Ca2+-选择性，线粒体离子通道（MCU）在快速连接感觉的信号通路中起着至关重要的作用病原体受体对吞噬体杀伤所需的代谢产物的影响。追寻这些诱人的线索现在已经奠定了坚实的科学基础来假设吞噬体-线粒体邻近的组装结构 (PMPA) 和线粒体 Ca2+ 信号传导增强细胞内在免疫力。在 Aim1 中，我们定义白色念珠菌触发线粒体-吞噬体相互作用的机制。在目标 2 中，我们定义激活的巨噬细胞中 mCa2+ 信号传导的调节机制。在目标 3 中，我们定义了关键驱动微生物杀灭的 mCa2+ 信号代谢输出。这项研究在概念上具有创新性，因为它揭示了病原体线粒体生理学、免疫代谢和微生物杀灭。创新包括监测初级巨噬细胞执行过程中 mCa2+ 升高的工具基于吞噬作用和电子断层扫描的线粒体-吞噬体相互作用的 3D 重建。这研究有可能揭示对其他专门的吞噬过程具有重要意义的设计原理例如清除凋亡细胞、有毒碎片和突触修剪。从转化/临床前的角度来看，我们的研究结果可能揭示新的免疫调节疗法的新分子靶点和途径。