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Role of the Macrophage in Developmentally Programmed NAFLD

巨噬细胞在发育程序性 NAFLD 中的作用

基本信息

批准号：
10206128
负责人：
JACOB E FRIEDMAN
金额：
$ 59.77万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206128
关键词：
Acetates Adult Adult Children Affect Age Agonist Anti-Inflammatory Agents Antioxidants Aryl Hydrocarbon Receptor Attenuated Bacteria Biological Assay Birth Bone Marrow Cell physiology Cells Child Chronic Disease Citric Acid Cycle Data Development Dietary Intervention Disease Disease Progression Elderly Embryo Epigenetic Process Exposure to Fatty Liver Fetal Liver Fostering Functional disorder Future Gene Expression Gene Expression Profile Genetic Transcription Germ-Free Goals Hematopoiesis Hematopoietic stem cells Hepatic Hepatic Fibrogenesis Hepatocyte Histology Homeostasis Human Human Milk Immune Immune response Immune system Impairment In Vitro Indoles Infant Inflammation Inflammation Mediators Inflammatory Innate Immune System Knock-out Knockout Mice Lactation Life Link Liver Liver Fibrosis Liver diseases Long-Term Effects Longevity Mediator of activation protein Metabolic Metabolism Microbe Molecular Mothers Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Nutritional Obese Mice Obesity Overnutrition PQQ Cofactor Pathway interactions Pattern Phenotype Physiology Play Pregnancy Pregnant Women Prevention Process Production Publications Receptor Activation Receptor Signaling Risk Role Serum Severities Stem Cell Development Supplementation Testing Therapeutic Time Tissues Treatment Cost Tryptophan Tryptophan Metabolism Pathway Work adult obesity aryl hydrocarbon receptor ligand bacterial metabolism base dietary disorder risk dysbiosis experimental study fibrogenesis gain of function good diet gut bacteria gut microbiota high risk improved in vivo innate immune function macrophage metabolic phenotype metabolomics metagenomic sequencing microbial microbiome microbiota monocyte mother nutrition non-alcoholic fatty liver disease nonhuman primate novel obese mothers obesity in children offspring postnatal pregnant preservation prevent progenitor recruit respiratory response single cell analysis transcription factor western diet

项目摘要

Specific Aim 1. Test the hypothesis that maternal WD during gestation and lactation regulates offspring myeloid cell function through distinct metabolic and/or transcriptional mechanisms that accelerate NAFLD risk across the offspring lifespan. 1a) We will test if WD during gestation or lactation induces changes in number, activation state, or functional responses of fetal liver monocytes (Mo)/Mφ and hematopoietic stem and progenitor cells (HSPCs) or adult offspring liver Mφ and if this can be rescued by cross-fostering to a chow (CH)- fed dam. Liver histology and metabolic phenotyping will be used to evaluate severity of NAFLD and metabolic adaptations at 16 wks of age. 1b) We will profile metabolites and glycolytic/TCA cycle respiratory activity in offspring liver Mφ and BMDM to test for re-programming of immunometabolism. 1c) We will determine the impact of maternal WD exposure on transcriptional and epigenetic adaptations in isolated liver Mo/Mφ and BMDMs in early life and during adulthood. Specific Aim 2. Test the hypothesis that decreased AHR signaling provides a mechanistic link between maternal WD dysbiosis, Mφ metabolic reprogramming, and NAFLD risk. 2a) We will supplement WD-fed dams with an indole-based AHR agonist to determine if restoring AHR signaling protects against maternal WD-induced myeloid dysfunction in offspring. 2b) We will profile transcriptional and epigenetic adaptations in liver Mo/Mφ in WD-exposed offspring with myeloid deletion (KO) of AHR and assess for Mφ functional changes and NAFLD progression. Specific Aim 3. Test the hypothesis that dietary PQQ promotes gut microbial metabolism of indoles that preserve Mφ function in offspring exposed to maternal WD. 3a) We will test if PQQ-exposed microbes transferred to CH-fed GF dams during gestation or lactation increases bacterial production of indoles in offspring.

具体目标 1. 检验以下假设：妊娠和哺乳期间母亲 WD 通过不同的代谢和/或转录机制调节后代骨髓细胞功能，从而加速后代一生中 NAFLD 的风险。 1a) 我们将测试妊娠或哺乳期间的 WD 是否会引起胎儿肝脏单核细胞 (Mo)/Mφ 和造血干细胞和祖细胞 (HSPC) 或成年后代肝脏 Mφ 的数量、激活状态或功能反应的变化，以及是否可以通过与松狮 (CH) 喂养的母鼠交叉寄养来挽救这种变化。肝脏组织学和代谢表型分析将用于评估 NAFLD 的严重程度和 16 周龄时的代谢适应。 1b) 我们将分析子代肝脏 Mφ 和 BMDM 中的代谢物和糖酵解/TCA 循环呼吸活动，以测试免疫代谢的重新编程。 1c) 我们将确定母亲 WD 暴露对生命早期和成年期间离体肝脏 Mo/Mφ 和 BMDM 转录和表观遗传适应的影响。具体目标 2. 检验 AHR 信号传导减少提供机制联系的假设母亲 WD 生态失调、Mφ 代谢重编程和 NAFLD 风险之间的关系。 2a) 我们将用基于吲哚的 AHR 激动剂补充 WD 喂养的母鼠，以确定恢复 AHR 信号是否可以防止母体 WD 诱导的后代骨髓功能障碍。 2b) 我们将分析 AHR 髓样缺失 (KO) WD 暴露后代肝脏 Mo/Mφ 的转录和表观遗传适应，并评估 Mφ 功能变化和 NAFLD 进展。具体目标 3. 检验膳食 PQQ 促进肠道微生物代谢的假设吲哚在暴露于母体 WD 的后代中保留 Mφ 功能。 3a) 我们将测试在妊娠或哺乳期间将暴露于 PQQ 的微生物转移到 CH 饲喂的 GF 母鼠中是否会增加后代中吲哚的细菌产量。