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.

项目摘要免疫系统的吞噬细胞需要迅速的能量来吞噬并及时杀死病原体方式。耗能大分子复合物，例如液泡ATPase（V-ATPase）和NADPH 氧化酶（NOX）复合物被募集到吞噬体中，以酸化，氧化，杀死和消化致病货物。通过基因表达对代谢机械的重新编程太慢，无法满足需求急剧增加用于能量和代谢物。哨兵吞噬细胞如何传递病原体的识别以切换细胞代谢的一级齿轮如此迅速？我们的初步数据表明CA2+选择性线粒体离子通道MCU在迅速连接感觉的信号通路中起着至关重要的作用病原体的受体杀死吞噬体所需的代谢输出。追求这些诱人的潜在客户现在已经奠定了强大的科学基础，可以假设吞噬小节的组合结构（PMPA）和线粒体Ca2+ - 信号燃料燃料细胞内部免疫。在AIM1中，我们定义了白色念珠菌触发的线粒体形状相互作用的基础机制。在AIM 2中，我们定义在活化的巨噬细胞中调节MCA2+信号的机制。在AIM 3中，我们定义了钥匙驱动微生物杀死的MCA2+信号的代谢输出。这项研究在概念上是创新的，因为它揭开了病原体线粒体生理，免疫代谢和微生物杀死。创新包括监视执行主要巨噬细胞中MCA2+高压的工具基于线粒体斑点相互作用的基于吞噬作用和电子层析成像的3D重建。这研究有可能揭示针对其他专业的吞噬过程显着的设计原理例如凋亡细胞，有毒碎屑和突触修剪的清除。从翻译/临床前的角度来看，我们的发现可能揭示了新的免疫调节疗法的新分子靶标和途径。