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.

项目概要尽管体重指数正常，但老年人的内脏脂肪增多，而且这种增加是与代谢疾病风险增加相关。脂肪分解是产生游离脂肪的第一步。酸和甘油作为能量底物，随着年龄的增长而减少，可能是导致能量增加的原因老年人肥胖导致脂肪分解减少的变化尚不清楚，但了解这些变化。可能提供恢复脂肪分解和减少老年人内脏肥胖的方法。对维持组织稳态至关重要的组织驻留细胞在衰老过程中其水平升高。炎症体激活和控制脂肪分解减少也随着衰老和纤维化的增加而增加。衰老，但它们是否有助于减少脂肪分解尚不清楚。生长分化因子 (GDF)-3，TGFβ 家族成员，作为脂肪分解的负调节因子以及衰老过程中炎症、衰老和纤维化的潜在触发因素。确定巨噬细胞表达的 GDF3 在促进炎症、衰老和纤维化中的作用，以驱动具体来说，我们建议 (1) 确定 GDF3 如何增加。 NLRP3 炎性体激活和脂解抗性，(2) 表征衰老巨噬细胞和确定 GDF3 是否驱动脂肪巨噬细胞衰老，以及 (3) 确定 GDF3 是否在目标 1 中，我们将鉴定激活素受体。以及 SMAD 信号传导是否会改变体外巨噬细胞中的炎症小体激活。体外结果并检查 GDF3 是否是年龄诱导的脂肪分解抵抗和炎症所必需的使用 Gdf3 缺陷的老年小鼠模型在目标 2 中，我们将使用独特的方法定义衰老巨噬细胞。转基因小鼠模型允许使用流式细胞术鉴定衰老细胞。由于 GDF3 的要求，我们将在转基因小鼠中删除 GDF3，以使用流式细胞仪分析脂肪巨噬细胞目标 3 将鉴定由细胞产生的细胞外基质蛋白。另外，Gdf3+/+ 和 Gdf3-/- 小鼠衰老模型和 RNA 的反应。测序将用于鉴定在脂肪纤维化中调节 GDF3 的新候选药物。该项目将确定 GDF3 在年龄诱导的脂肪分解抵抗中的作用，并作为潜在的治疗人类衰老过程中的炎症和脂肪分解抵抗的治疗目标。候选人的目标是获得独立的学术生涯，研究重点是理解衰老过程中脂肪功能障碍的驱动机制。