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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：
10627890
负责人：
JACOB E FRIEDMAN
金额：
$ 51.18万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627890
关键词：
Acceleration Acetates Adult Adult Children Affect Age Agonist Anti-Inflammatory Agents Antioxidants Aryl Hydrocarbon Receptor Attenuated Bacteria Birth Bone Marrow Cell physiology Child Chronic Disease Citric Acid Cycle Data Development Dietary Intervention Disease Disease Progression Elderly Epigenetic Process Exposure to Fetal Liver Fostering Functional disorder Future Gene Expression Profile Genetic Transcription Germ-Free Goals Hematopoietic stem cells Hepatic Hepatic Fibrogenesis Hepatocyte Histology Homeostasis Human Human Milk Immune system Impairment Indoles Infant Inflammation Inflammation Mediators Inflammatory Innate Immune System Knock-out Knockout Mice Lactation Life Link Liver Liver diseases Longevity Macrophage Metabolic Metabolism Microbe Molecular Mothers Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Nutritional Obese Mice Obesity Overnutrition PQQ Cofactor Pathway interactions Phenotype Play Pregnancy Pregnant Women Process Production Publications Receptor Activation Receptor Signaling Role Severities Stem Cell Development Supplementation Testing Therapeutic Time Tissues Treatment Cost Tryptophan Tryptophan Metabolism Pathway Work adult obesity aryl hydrocarbon receptor ligand bacterial metabolism cofactor dietary disorder risk dysbiosis experimental study fatty liver disease gut bacteria gut microbiota high risk improved innate immune function metabolic phenotype microbial microbiome monocyte mother nutrition non-alcoholic fatty liver disease nonhuman primate novel obese mothers obesity in children offspring postnatal preservation prevent progenitor programs recruit respiratory response 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.

具体目标验证母体妊娠和哺乳期WD通过不同的代谢和/或转录机制调节后代髓细胞功能的假设，从而加速后代一生中NAFLD的风险。