Regulation of innate immune cell responses through cell-to-cell transfer of mitochondria

通过线粒体细胞间转移调节先天免疫细胞反应

基本信息

批准号：
10018959
负责人：
Jonathan R Brestoff
金额：
$ 39.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018959
关键词：
Address Adipocytes Adipose tissue Adoptive Cell Transfers Adult Affect Award Biological Assay Biomedical Research Blood Circulation Bone Marrow Transplantation Cells Child Clustered Regularly Interspaced Short Palindromic Repeats Communities Core Facility Creativeness Cytokine Activation Data Development Diet Disease EXT1 gene Energy Metabolism Environment Fatty acid glycerol esters Flow Cytometry Foreign Bodies Genes Genetic Models Genus Hippocampus Glucose Healthcare Systems Heart Diseases Heparitin Sulfate High Fat Diet Homeostasis Human Hypertrophy Immune Immunologics Immunology Impairment In Vitro Inflammation Inflammatory Knock-out Laboratories Laboratory Study Lead Link Lipids Malignant Neoplasms Mentors Metabolic Metabolic Diseases Metabolism Mitochondria Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obese Mice Obesity Pathologic Pathology Pathway interactions Physicians Physiological Processes Population Process Public Health Publications Regulation Reporter Research Resources Role Scientist Surface Testing Therapeutic Thinness Tissues Transcriptional Activation Transplantation Uncertainty United States Universities Vision Washington Work career career development cell type cost cytokine falls genome-wide immunoregulation improved in vivo innovation insulin sensitivity lipid metabolism macrophage medical schools mitochondrial dysfunction novel novel therapeutic intervention obesity development prevent professor programs response skills tenure track transcriptome sequencing uptake

项目摘要

PROJECT SUMMARY Obesity is an increasingly prevalent metabolic disease that affects 38% of adults and 16% of children and costs the United States healthcare system nearly $200 billion annually. Consequently, there is an urgent need to better understand the factors that regulate the development of obesity. Emerging studies indicate that white adipose tissue (WAT)-resident immune cell populations critically regulate the development of obesity by producing cytokines that modulate glucose utilization, lipid storage, and energy expenditure. However, despite our growing understanding of the influence of immune cells on obesity, how metabolic cells such as adipocytes control immune cell responses remains poorly defined. In preliminary studies, I have identified that adipocytes transfer their mitochondria to a subset of macrophages in WAT in vivo, potentially defining a new macrophage population. Strikingly, this process is impaired in high fat diet (HFD)-induced obesity. Further, mitochondria transplantation to mice results in tissue-specific accumulation of macrophages in WAT and release of free fatty acids into circulation. These observations suggest that intercellular mitochondria transfer is a dynamically regulated physiologic process that has important functional effects on lipid metabolism. To dissect the mechanisms of intercellular mitochondria transfer, I performed a genome-wide CRISPR-knockout screen. The top-scoring gene, Exostosis 1 (Ext1), is required for heparan sulfate synthesis and is essential for normal lipid metabolism in mice and humans. Critically, my data indicate that Ext1 is necessary for mitochondria transfer in vitro without affecting uptake of other foreign bodies. Collectively, these data provoke the central hypothesis that intercellular transfer of mitochondria from adipocytes to macrophages is a previously unrecognized mechanism that controls macrophage function and systemic metabolic homeostasis. This hypothesis forms the basis of my two aims. In Aim 1, I will determine the identity and function of macrophages that have acquired mitochondria from adipocytes and investigate the immunologic and metabolic potential of these cells. In Aim 2, I will investigate whether EXT1 is required for intercellular mitochondrial transfer and regulation of metabolic homeostasis in vivo. These will be addressed employing the intellectual and scientific resources available in the Brestoff lab, novel strains of mitochondria reporter mice, new genetic models of disrupted mitochondria transfer, and a suite of metabolism and immunology core facilities at Washington University School of Medicine. Importantly, these findings may impact how we approach the treatment of metabolic disorders beyond existing therapeutic paradigms.

项目概要肥胖是一种日益普遍的代谢性疾病，影响 38% 的成人和 16% 的儿童，并造成高昂的费用美国医疗保健系统每年花费近2000亿美元。因此，迫切需要更好地了解调节肥胖发展的因素。新兴研究表明，白色脂肪组织（WAT）驻留免疫细胞群通过产生调节葡萄糖利用、脂质储存和能量消耗的细胞因子。然而，尽管我们人们越来越了解免疫细胞对肥胖的影响，以及代谢细胞（例如脂肪细胞控制免疫细胞反应的定义仍然不明确。在初步研究中，我已经确定脂肪细胞将其线粒体转移到体内 WAT 中的巨噬细胞子集，这可能定义了一种新的巨噬细胞群。引人注目的是，这一过程在高脂肪饮食（HFD）引起的肥胖中受到损害。更远，小鼠线粒体移植导致 WAT 中巨噬细胞的组织特异性积累和释放游离脂肪酸进入循环。这些观察结果表明细胞间线粒体转移是一种动态调节的生理过程，对脂质代谢具有重要的功能影响。剖析为了了解细胞间线粒体转移的机制，我进行了全基因组 CRISPR 敲除筛选。得分最高的基因 Exostosis 1 (Ext1) 是硫酸乙酰肝素合成所必需的，并且对于正常细胞至关重要。小鼠和人类的脂质代谢。重要的是，我的数据表明 Ext1 对于线粒体转移是必需的在体外不影响其他异物的摄取。总的来说，这些数据引发了中心假设线粒体从脂肪细胞到巨噬细胞的细胞间转移是以前未被认识到的控制巨噬细胞功能和全身代谢稳态的机制。这个假设形成了我的两个目标的基础。在目标 1 中，我将确定已获得的巨噬细胞的身份和功能来自脂肪细胞的线粒体，并研究这些细胞的免疫和代谢潜力。在目标 2 中，我将研究 EXT1 是否是细胞间线粒体转移和代谢调节所必需的体内稳态。这些问题将利用现有的知识和科学资源来解决。布雷斯托夫实验室，线粒体报告小鼠的新品种，线粒体转移中断的新遗传模型，以及华盛顿大学医学院的一套代谢和免疫学核心设施。重要的是，这些发现可能会影响我们在现有的基础上治疗代谢紊乱的方法治疗范式。