Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose

老年脂肪巨噬细胞炎症小体激活及抗脂解机制

基本信息

批准号：
10121181
负责人：
Christina Camell
金额：
$ 36.83万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2019-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10121181
关键词：
Adipose tissue Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Animals Atherosclerosis Automobile Driving Cells Cerebrum Complement Data Dementia Diabetes Mellitus Differentiation and Growth Elderly Exposure to Extracellular Matrix Family Fatty Acids Fibrosis Funding Genetic Transcription Human Immune Impairment Inflammaging Inflammasome Inflammation Lead Lipolysis Metabolic Metabolic Diseases Microglia Molecular Mus Myelogenous Neurocognitive Deficit Neurodegenerative Disorders Neurons Obesity Pathology Pathway interactions Patients Pattern Production Proteins Publications Resistance Risk Role Signal Pathway Testing Tissues Transforming Growth Factor beta Transgenic Mice Visceral age related aged amyloid pathology cognitive function growth differentiation factor 3 in vivo macrophage member neurogenesis neuroinflammation senescence

项目摘要

Project Summary Increased visceral adiposity and inflammation seen in the elderly are associated with elevated risk for metabolic diseases, such as diabetes and atherosclerosis. Moreover, inflammaging and metabolic disease are correlated with increased risk to develop dementia and neurodegenerative diseases including Alzheimer’s disease (AD). One major overlapping pathway driving both metabolic and Alzheimer’s disease is the NLRP3 inflammasome pathway, which becomes activated in myeloid and macrophage-like cells following exposure to a wide range of damage associated molecular patterns, like fatty acids and amyloid-beta (Aβ). Tissue resident macrophages control homeostatic functions that are disrupted during aging. Our data reveals adipose macrophage transcriptional changes lead to impaired lipolysis in aged visceral adipose tissue. We identified macrophage-expressed growth differentiation factor (GDF)-3, a member of the TGFβ family, as a negative regulator of adipose lipolysis and driver of NLRP3 inflammasome activation and aging-pathologies. Our ongoing project examines the role for macrophage-expressed GDF3 in increasing inflammation, senescence and fibrosis to aggravate tissue functioning in the aged adipose tissue. The specifics aims, which are unchanged, of this project include (1) determine how GDF3 increases NLRP3 inflammasome activation and lipolysis resistance, (2) characterize senescent macrophages and then determine whether GDF3 drives senescence in adipose tissue immune cells, and (3) identify whether GDF3 is required for ECM production and increased fibrosis in aged adipose. Aβ activates the NLRP3 inflammasome driving microglial inflammation, Aβ-pathology and neurocognitive impairments. In this supplement we propose to investigate GDF3 as an activator of Nlrp3 inflammasome-driven neuroinflammation and cerebral amyloid pathology. In unexpected findings, TGFb/GDF signaling pathway and GDF3 protein are reduced in human patients with AD, potentially by limiting neurogenesis. Thus it will be critical to test whether GDF3-deficiency regulates inflammasome activation in specific cells. To identify whether GDF3 controls inflammasome activation, a widely used transgenic mouse model of AD, (5xFAD mice), expressing or with GDF3-deficiency will be used to evaluate neuroinflammation, AD-pathology and cognitive function. To complement in vivo studies, inflammasome activation in primary microglia and neurons from GDF3-expressing or deficient animals will be evaluated in the presence or absence of Aβ. Together, these projects will study GDF3-deficiency in age-related inflammasome activation during metabolic disease and Alzheimer’s disease. This project is well-situated to generate publications and preliminary data supporting additional funding for investigating the GDF3-NLRP3 inflammasome axis in AD-pathology

项目概要老年人内脏脂肪增多和炎症增加与罹患癌症的风险升高相关代谢疾病，例如糖尿病和动脉粥样硬化，此外，还有炎症和代谢疾病。与患痴呆症和神经退行性疾病（包括阿尔茨海默病）的风险增加相关导致代谢病和阿尔茨海默病 (AD) 的一个主要重叠途径是 NLRP3。炎症小体途径，在暴露于一系列与分子模式相关的损伤，如脂肪酸和β-淀粉样蛋白 (Aβ)。我们的数据显示，组织驻留巨噬细胞控制着衰老过程中被破坏的稳态功能。脂肪巨噬细胞转录变化导致衰老内脏脂肪组织的脂解作用受损。鉴定出巨噬细胞表达的生长分化因子 (GDF)-3（TGFβ 家族的成员）作为脂肪分解的负调节因子以及 NLRP3 炎症小体激活和衰老病理学的驱动因子。我们正在进行的项目研究巨噬细胞表达的 GDF3 在增加炎症中的作用，衰老和纤维化会加剧老化脂肪组织的功能。未改变，该项目包括 (1) 确定 GDF3 如何增加 NLRP3 炎症小体激活和脂肪分解抗性，（2）表征衰老巨噬细胞，然后确定 GDF3 是否驱动脂肪组织免疫细胞的衰老，以及 (3) 确定 GDF3 是否是 ECM 产生所必需的老化脂肪纤维化增加。 Aβ 激活 NLRP3 炎症小体，驱动小胶质细胞炎症、Aβ 病理学和神经认知在本补充材料中，我们建议研究 GDF3 作为 Nlrp3 炎症小体驱动的激活剂。神经炎症和脑淀粉样蛋白病理学的意外发现，TGFb/GDF 信号通路和 GDF3 蛋白在人类 AD 患者中减少，可能是通过限制神经发生来实现的。测试 GDF3 缺陷是否调节特定细胞中的炎症小体激活至关重要。 GDF3 控制炎症小体激活，这是一种广泛使用的 AD 转基因小鼠模型（5xFAD 小鼠），表达或缺乏 GDF3 将用于评估神经炎症、AD 病理学和认知为了补充体内研究，初级小胶质细胞和神经元中的炎症小体激活。 GDF3 表达或缺陷的动物将在 Aβ 存在或不存在的情况下进行评估。项目将研究代谢疾病期间与年龄相关的炎症小体激活中的 GDF3 缺陷，以及该项目非常适合产生出版物和初步数据支持。用于研究 AD 病理学中 GDF3-NLRP3 炎性体轴的额外资金