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：
10190757
负责人：
Christina Camell
金额：
$ 24.38万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190757
关键词：
Activin Receptor Adipocytes Adipose tissue Age Aging Automobile Driving Body Temperature Body mass index CASP1 gene Catecholamines Cells Chronic Disease Data Defect Diet Elderly Extracellular Matrix Extracellular Matrix Proteins Failure Family Fatty Acids Fibrosis Flow Cytometry Functional disorder Gene Expression Generations Genes Glycerol Goals Homeostasis Human Hydrolysis In Vitro Inflammaging Inflammasome Inflammation Inflammatory Insulin Resistance Interleukin-1 beta Lead Ligation Lipids Lipolysis Lipopolysaccharides Messenger RNA Metabolic Diseases Mus Nonesterified Fatty Acids Obesity Outcome Pathway interactions Process Production Regulation Research Resistance Risk Role Signal Transduction Starvation Stress Testing Tissues Transforming Growth Factor beta Transgenic Mice Triglycerides Visceral aged base career design end of life exercise capacity experimental study growth differentiation factor 3 healthspan improved macrophage marenostrin member mouse model novel receptor response senescence therapeutic target transcriptome sequencing

项目摘要

Project Summary Visceral adiposity is increased in the elderly, despite a normal body-mass-index, and this increase is associated with increased risk for metabolic diseases. Lipolysis is the first step in the generation of free fatty acids and glycerol as energy substrates, is reduced with age and may be responsible for the increased adiposity in the elderly. The changes that drive reduced lipolysis are unclear, but understanding those changes may provide ways to restore lipolysis and reduce visceral adiposity in the elderly. Adipose macrophages are tissue resident cells that are critical in maintaining tissue homeostasis. During aging they have elevated levels of inflammasome activation and control lipolysis reduction. Senescence and fibrosis are also increased with aging, but whether they contribute to reduced lipolysis is unclear. We have identified macrophage-expressed growth differentiation factor (GDF)-3, a member of the TGFβ family, as a negative regulator of adipose lipolysis and potential trigger of inflammation, senescence and fibrosis in aging. The overall goal of this study is to identify the role for macrophage-expressed GDF3 in promoting inflammation, senescence and fibrosis to drive lipolysis resistance in the aged adipose tissue. Specifically, we propose to (1) determine how GDF3 increases NLRP3 inflammasome activation and lipolysis resistance, (2) characterize senescent macrophages and the determine whether GDF3 drives senescence in adipose macrophages and (3) identify whether GDF3 is required for ECM production and increased fibrosis in aged adipose. In Aim 1, we will identify activin receptors and whether SMAD signaling alters inflammasome activation in macrophages in vitro. We will extend these in vitro results and examine whether GDF3 is required for age-induced lipolysis resistance and inflammation using aged mouse models of Gdf3-deficiency. In Aim 2, we will define senescent macrophages using a unique transgenic mouse model permitting the identification of senescent cells using flow cytometry. To test for a requirement of GDF3, we will delete GDF3 in the transgenic mice to analyze adipose macrophages using flow cytometry and gene expression. Aim 3 will identify extracellular matrix proteins that are produced by macrophages in response to GDF3. Additionally, Gdf3+/+ and Gdf3-/- mouse models of aging and RNA sequencing will be used to identify novel candidates regulating GDF3 in adipose fibrosis. Completion of this project will permit identification of the role for GDF3 in age-induced lipolysis resistance and as a potential therapeutic target in treatment of inflammation and lipolysis resistance for humans during aging. The long term goals of the candidate are to obtain an independent academic career with research focused on understanding the mechanisms driving adipose dysfunction in aging.

项目摘要内脏肥胖在古老的情况下增加，做一个正常的身体质量索引，这种增加是与代谢疾病的风险增加有关。脂解是自由脂肪的第一步酸和甘油作为能量底物，随着年龄的增长而减少，可能导致增加肥胖的肥胖。减少脂解的变化尚不清楚，但是了解这些变化可以提供恢复脂解和减少较早的内脏肥胖的方法。脂肪巨噬细胞是组织居民细胞对维持组织稳态至关重要。在衰老期间，他们的水平升高炎性体激活和控制脂解的减少。衰老和纤维化也随之增加衰老，但是它们是否有助于减少脂解。我们已经确定了巨噬细胞表达的生长分化因子（GDF）-3，TGFβ家族的成员，作为脂肪脂解的负调节剂以及衰老中感染，感应和纤维化的潜在触发因素。这项研究的总体目标是确定巨噬细胞表达的GDF3在促进感染，感应和纤维化中的作用老化的脂肪组织中的脂解抗性。具体而言，我们建议（1）确定GDF3如何增加 NLRP3炎性体激活和脂解耐药性，（2）表征感觉巨噬细胞和确定GDF3是否驱动脂肪巨噬细胞中的感受，（3）确定GDF3是否为 ECM生产所需的脂肪和纤维化增加所必需的。在AIM 1中，我们将识别激活素受体 SMAD信号传导是否会改变体外巨噬细胞中的炎性体激活。我们将把这些扩展到体外结果并检查是否需要GDF3才能诱导年龄诱导的脂解和注射使用GDF3缺乏症的老鼠模型。在AIM 2中，我们将使用独特的转基因小鼠模型允许使用流式细胞仪鉴定感觉细胞。测试一个 GDF3的需求，我们将在转基因小鼠中删除GDF3，以使用流量分析脂肪巨噬细胞细胞仪和基因表达。 AIM 3将识别由细胞外基质蛋白响应GDF3的巨噬细胞。此外，gdf3+/+和gdf3 - / - 老化和RNA的小鼠模型测序将用于鉴定调节脂肪纤维化中GDF3的新型候选者。完成此操作项目将允许在年龄引起的脂肪分解抗性中识别GDF3的作用在衰老过程中，治疗感染和脂解耐药性的治疗靶标。长期候选人的目标是通过研究专注于理解的独立学术职业在衰老中驱动脂肪功能障碍的机制。