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

基本信息

批准号：
9371661
负责人：
Michael Lawrence Dougan
金额：
$ 17.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/9371661
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 Cessation of life Clinical Code Cytoplasmic Tail Data Diabetes Mellitus Energy Metabolism Enzymes 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 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

项目摘要

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：项目总结/摘要包括肥胖和二型糖尿病在内的代谢性疾病现已成为全球健康问题，且发病率不断上升流行率。产热棕色和米色脂肪已被提议作为新疗法的目标基于动物模型的代谢疾病已显示这些组织在对这两种疾病的易感性中发挥作用糖尿病肥胖。我们有令人兴奋的初步数据显示免疫调节的表达小鼠棕色脂肪内的蛋白质程序性死亡配体 1 (PD-L1)。我们发现PD-功能丧失 L1 导致调节棕色脂肪内脂肪代谢和线粒体生物发生的基因发生变化，并且这些变化与核心体温升高以及令人惊讶的风险增加有关当小鼠接受高脂肪饮食时体重增加。 PD-L1作为一种新的治疗药物受到了临床的广泛关注。使肿瘤逃避宿主免疫的核心组成部分；使用阻断 PD-的抗体进行免疫治疗 L1 或其受体程序性死亡 1 (PD-1) 在临床上用于治疗黑色素瘤、肺癌和膀胱癌。 PD-1/PD-L1 通路与肿瘤和免疫细胞的代谢变化有关。对它们做出反应，开启了针对该途径的治疗可能直接影响这些细胞的生长和复制。从而更深入地了解PD-L1对代谢的调节具有重大的临床意义。我们假设 PD-L1 直接调节棕色脂肪功能，改变热量产生并改变肥胖风险。进一步了解PD-L1在棕色脂肪中的作用显然，我们建议首先培育一种新型小鼠品系，其棕色脂肪中的 PD-L1 被特异性去除之前的实验中，细胞本身的 PD-L1 缺陷在整个小鼠中都是一致的。这些棕色脂肪特异性 PD-L1 缺陷动物对于明确证明其直接作用是必要的。 PD-L1 在棕色脂肪代谢中的作用。类似地，我们将生成 PD-L1 细胞内尾部已被去除的小鼠。仅在棕色脂肪中去除；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。我们将检查这些新小鼠品系对肥胖的易感性和产热情况；我们还将使用更复杂的能量消耗和喂养跟踪来了解驱动力这些动物肥胖风险升高的背后。该项目的第二个目标是描述 PD-L1 缺陷棕色脂肪中蛋白质表达和代谢中间体的变化，以揭示 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 的代谢组学观察全身 PD-L1 缺陷小鼠的棕色脂肪，以及新颖的该项目中产生了棕色脂肪特异性 PD-L1 缺陷小鼠。该项目的长期目标是阐明 PD-L1 在代谢疾病调节中的功能，这应该具有以下意义：仅用于体重调节，但也可能用于癌症免疫治疗。