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

• 批准号: 10247512
• 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
• 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/10247512
• 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; diet-induced obesity; 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

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.

项目摘要 肥胖是一种越来越普遍的代谢疾病，影响了38％的成年人和16％的儿童和成本 美国医疗体系每年将近2000亿美元。因此，迫切需要更好 了解调节肥胖发展的因素。新兴研究表明白脂肪 组织（WAT） - 居民免疫细胞种群通过产生批判性调节肥胖的发展 调节葡萄糖利用，脂质储存和能量消耗的细胞因子。但是，尽管我们 对免疫细胞对肥胖的影响的了解不断提高，如何代谢细胞（例如 脂肪细胞控制免疫细胞反应的定义较差。在初步研究中，我已经确定了 脂肪细胞将其线粒体转移到体内WAT中的巨噬细胞子集中，有可能定义一个新的 巨噬细胞种群。令人惊讶的是，高脂饮食（HFD）诱导的肥胖症受损。更远， 线粒体向小鼠的移植导致WAT中巨噬细胞的组织特异性积累并释放 游离脂肪酸的循环。这些观察结果表明细胞间线粒体转移是一个 动态调节的生理过程对脂质代谢具有重要的功能作用。剖析 我进行了细胞间线粒体转移的机制，我进行了全基因组CRISPR-KNOCKOUT屏幕。 得分最高的基因Exostosis 1（Ext1）是硫酸乙酰肝素合成所必需的，对于正常是必不可少的 小鼠和人类的脂质代谢。至关重要的是，我的数据表明ext1是线粒体传输所必需的 体外而不会影响其他异物的吸收。总的来说，这些数据引起了中心假设 线粒体从脂肪细胞向巨噬细胞的细胞间转移是先前未被认可的 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AIM 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了这些细胞的免疫和代谢潜力。在AIM 2中， 我将研究是否需要Ext1进行细胞间线粒体转移和代谢的调节 体内稳态。这些将采用可用的智力和科学资源来解决 Brestoff Lab，线粒体报告的新型菌株，线粒体转移的新遗传模型，线粒体转移的新遗传模型， 华盛顿大学医学院的一套新陈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如何处理现有的代谢疾病的治疗 治疗范例。