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.

具体目的1。检验以下假设：妊娠和泌乳过程中的材料WD通过不同的代谢和/或转录机制来调节髓样细胞功能，这些机制在后代寿命中加速NAFLD风险。 1A）我们将测试WD在妊娠或泌乳过程中是否诱导胎儿肝单核细胞（MO）/Mφ和造血干细胞（HSPCS）（HSPCS）或成人后代Mφ的数量，激活状态或功能反应的变化，如果可以通过交叉形成肝脏（CHOW（CH） - CHOW（CH） - CHOW（CH） - CHOW（CH） - CHOW（CH）。肝组织学和代谢表型将用于评估NAFLD的严重程度和年龄16周的代谢适应性。 1B）我们将在后代肝Mφ和BMDM中介绍代谢物和糖酵解/TCA循环呼吸活性，以测试重新编程免疫代谢。 1C）我们将在早期和成年期确定母体WD暴露对分离的肝MO/Mφ和BMDMS中转录和表观遗传适应的影响。具体目标2。测试降低AHR信号传导的假设提供了机械链接在产妇WD失调，Mφ代谢重编程和NAFLD风险之间。 2A）我们将用基于吲哚的AHR激动剂补充WD喂养的大坝，以确定恢复AHR信号是否可以防止MATER WD诱导的后代中的髓样功能障碍。 2b）我们将以AHR的髓样缺失（KO）和Mφ功能变化和NAFLD进展的评估，在WD暴露后代的肝MO/Mφ中介绍转录和表观遗传适应。特定目的3。检验饮食PQQ促进肠道微生物代谢的假设在暴露于材料WD的后代中保留Mφ功能的吲哚。 3A）我们将测试在妊娠或泌乳过程中转移到CH-FED GF大坝上的PQQ暴露的微生物是否会增加后代吲哚的细菌产生。