Mitochondrial Calcium Signaling in Cell Intrinsic Immunity

细胞内在免疫中的线粒体钙信号传导

• 批准号: 10297192
• 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
• 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/10297192
• 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; Immune system; Immunity; Immunologics; Infection; Inflammatory; Ion Channel; Lead; Lipids; Macromolecular Complexes; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Matrix; Molecular; Molecular Machines; Molecular Target; Monitor; Movement; Mus; Myeloid Cells; NADP; NADPH Oxidase; Neuromuscular Diseases; Organelles; Output; Oxides; 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; Structure; Synapses; Testing; Time; Ubiquitination; antimicrobial; base; calcium uniporter; design; electron tomography; fascinate; fighting; immunomodulatory therapies; immunoregulation; in vivo; innovation; interest; light microscopy; macrophage; microbial; mitochondrial membrane; mitochondrial metabolism; novel; pathogen; pathogenic fungus; pathogenic microbe; pre-clinical; pyruvate dehydrogenase; reconstruction; recruit; response; stoichiometry; synaptic pruning; tool; vacuolar H+-ATPase

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.

项目摘要 免疫系统的吞噬细胞需要快速爆发的能量来及时吞噬和杀死病原体。 方式需要能量的大分子复合物，如液泡ATP酶（V-ATP酶）和NADPH 氧化酶（NOX）复合物被募集到吞噬体中以酸化、氧化、杀死和消化病原性货物。 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 获取能量和代谢物哨兵吞噬细胞如何传递病原体的识别，以切换 细胞新陈代谢的主要齿轮如此之快？我们的初步数据表明，钙选择性， 线粒体离子通道（MCU）在快速连接感觉神经元的信号通路中起着至关重要的作用。 病原体的受体对吞噬体杀伤所必需的代谢产物的作用。追踪这些诱人的线索 现在已经奠定了一个强大的科学基础，假设吞噬体-线粒体接近的组装 PMPA和线粒体Ca 2+信号传导促进细胞固有免疫。在Aim 1中，我们定义了 C.白色念珠菌。在目标2中，定义 mCa 2 +-信号传导在活化的巨噬细胞中调节的机制。在目标3中，我们定义了密钥 mCa 2+信号的代谢输出驱动微生物杀灭。这项研究在概念上是创新的，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原代巨噬细胞中mCa 2+升高的工具， 吞噬作用和基于电子断层扫描的线粒体-吞噬体相互作用的3D重建。的 研究有可能揭示对其他专门的吞噬过程具有显著意义的设计原则 例如清除凋亡细胞、毒性碎片和突触修剪。从转化/临床前的角度来看， 我们的发现可能揭示新免疫调节疗法的新分子靶点和途径。