Regulation of brown fat metabolism by the immune receptor PD-L1

免疫受体 PD-L1 对棕色脂肪代谢的调节

• 批准号: 9766279
• 负责人: Michael Lawrence Dougan
• 金额: $ 17.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766279
• 关键词: Acetyl-CoA Carboxylase; Adipocytes; Adipose tissue; Animal Model; Animals; Antineoplastic Agents; Attention; Biogenesis; Bladder; Blocking Antibodies; Body Temperature; Body Weight; Brown Fat; Cell Line; Cells; Clinical; Code; Cytoplasmic Tail; Data; Diabetes Mellitus; Energy Metabolism; Enzymes; Exposure to; Fatty acid glycerol esters; Foundations; Generations; Genes; Goals; Growth; Hematopoietic; High Fat Diet; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunoblotting; Immunologic Receptors; Immunotherapy; Insulin; Invaded; Knock-out; Knockout Mice; Knowledge; Life; Link; Lipids; Lung; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mission; Mitochondria; Molecular; Monoclonal Antibodies; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; PDCD1LG1 gene; Pathway interactions; Phenotype; Physicians; Physiologic Thermoregulation; Predisposition; Prevalence; Production; Public Health; Regulation; Research; Risk; Role; SLEB2 gene; Scientist; Section 8; Signal Transduction; Signaling Protein; Tail; Temperature; Therapeutic; TimeLine; Tissues; Transgenic Mice; United States National Institutes of Health; Weight Gain; base; cancer immunotherapy; cancer therapy; career; driving force; experimental study; feeding; genetic regulatory protein; global health; interest; lipid metabolism; liquid chromatography mass spectrometry; loss of function; medical schools; melanoma; metabolomics; mouse model; new therapeutic target; novel; obesity risk; pre-clinical; protein expression; receptor; targeted treatment; therapeutic target; tumor; tumor metabolism

Section 7: Project Summary/Abstract Metabolic diseases including obesity and type II diabetes are now global health concerns with a rising prevalence. Heat producing brown and beige fat have been proposed as targets for novel therapies to treat metabolic diseases based on animal models that have shown a role for these tissues in susceptibility to both obesity of diabetes. We have provocative preliminary data that show expression of the immune regulatory protein programmed death ligand 1 (PD-L1) within the brown fat of mice. We found that loss of function of PD- L1 led to changes in genes that regulate fat metabolism and mitochondrial biogenesis within the brown fat, and that these changes were associated with increased core body temperature and a surprising increased risk of weight gain when the mice were exposed to a high-fat diet. PD-L1 has achieved much clinical attention as a central component in enabling tumors to evade host immunity; immune therapy using antibodies that block PD- L1 or its receptor programmed death 1 (PD-1) are in clinical use to treat melanoma, lung and bladder cancer. The PD-1/PD-L1 pathway has been linked to metabolic changes in both tumors and the immune cells that respond to them, opening up the possibility that therapies targeting this pathway may directly influence the growth and replication of these cells. Thus a deeper understanding of the regulation of metabolism by PD-L1 is of substantial clinical interest. We hypothesize that PD-L1 directly regulates brown fat function, altering heat generation and modifying the risk of obesity. To understand the role of PD-L1 in brown fat more clearly, we propose first to generate a novel strain of mice with PD-L1 specifically removed in the brown fat cells themselves as prior experiments have been done with PD-L1 deficiency uniform across the whole mouse. These brown fat specific PD-L1 deficient animals are necessary to unequivocally demonstrate a direct role for PD-L1 in brown fat metabolism. Similarly, we will generate mice where the intracellular tail of PD-L1 has been removed only in brown fat; these animals will enable us to look for direct PD-L1 signaling in the regulation of brown fat. We will examine both susceptibility to obesity, and heat generation in these novel mouse strains; we will also use more sophisticated tracking of energy expenditure and feeding to understand the driving forces behind the elevated obesity risk in these animals. The second goal of this project is to characterize the changes in protein expression and metabolic intermediates in PD-L1 deficient brown fat to uncover the molecular mechanism by which PD-L1 regulates brown fat. These experiments will use immunoblotting and LC/MS based metabolomics to look at brown fat from total body PD-L1 deficient mice, as well as the novel brown fat specific PD-L1 deficient mice generated in this project. The long-term goal of this project is to elucidate the function of PD-L1 in regulation of metabolic disease, which should have implications not only for the regulation of body weight, but potentially for cancer immunotherapy as well.

第7节：项目摘要/摘要 现在，包括肥胖和II型糖尿病在内的代谢疾病现在是全球健康问题，随着增长 流行率。已经提出了热产生棕色和米色脂肪作为治疗新疗法的靶标 基于动物模型的代谢疾病，这些疾病表现出这些组织在敏感性上发挥作用的作用 糖尿病的肥胖症。我们有挑衅性的初步数据，显示免疫调节的表达 蛋白质编程的死亡配体1（PD-L1）在小鼠的棕色脂肪中。我们发现PD的功能丧失 L1导致调节脂肪代谢和线粒体生物发生的基因变化，棕色脂肪和线粒体生物发生 这些变化与核心体温升高以及令人惊讶的增加的风险有关 当小鼠暴露于高脂饮食时，体重增加。 PD-L1作为一个临床关注 使肿瘤能够逃避宿主免疫的中心部分；使用阻断PD-的抗体免疫治疗 L1或其受体程序死亡1（PD-1）用于治疗黑色素瘤，肺癌和膀胱癌。 PD-1/PD-L1途径与肿瘤和免疫细胞的代谢变化有关 对他们的回应，打开针对该途径的治疗可能直接影响的可能性 这些细胞的生长和复制。因此，对PD-L1对代谢的调节的更深入的了解是 具有很大的临床意义。我们假设PD-L1直接调节棕色脂肪功能，改变 热产生并改变肥胖风险。了解PD-L1在棕色脂肪中的作用更多 显然，我们首先提出，在棕色脂肪中特异性去除的PD-L1产生新的小鼠菌株 细胞本身作为先前的实验，已在整个小鼠中使用PD-L1缺陷均匀。 这些棕色脂肪特异性PD-L1不足动物对于明确表现出直接作用是必要的 棕色脂肪代谢中的PD-L1。同样，我们将生成小鼠PD-L1的细胞内尾巴 仅以棕色脂肪去除；这些动物将使我们能够在调节中寻找直接的PD-L1信号传导 棕色脂肪。我们将检查这些新型小鼠菌株中对肥胖症的敏感性和热量产生。我们 还将使用更复杂的能量支出和喂食来了解驱动力 这些动物的肥胖风险升高的背后。该项目的第二个目标是表征 PD-L1缺乏棕色脂肪中蛋白质表达和代谢中间体的变化，以发现 PD-L1调节棕色脂肪的分子机制。这些实验将使用免疫印迹和 基于LC/MS的代谢组学以查看总体PD-L1缺陷小鼠的棕色脂肪以及新颖 该项目中产生的棕色脂肪特异性PD-L1缺乏小鼠。该项目的长期目标是 阐明PD-L1在调节代谢疾病中的功能，这应该有意义而不是 仅用于调节体重，但也有可能用于癌症免疫疗法。