Characterization of the Fetal Primate Epigenome and Metabolome Under In Utero

子宫内胎儿灵长类动物表观基因组和代谢组的表征

基本信息

批准号：
7428765
负责人：
Kjersti Marie Aagaard
金额：
$ 230.25万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7428765
关键词：
5&apos Flanking Region ADP ribosylation Acetylation Acids Address Adipose tissue Adolescent Adult Adult Children Affect Age-Months Alanine Transaminase Amino Acids Animal Feed Animal Model Animals Antibodies Area Arginine Arteries Arts Authorization documentation Autopsy Award Back Barker Hypothesis Base Sequence Basic Science Behavior Therapy Betaine Bilateral Binding Biological Process Biology Biomedical Research Biopsy Birth Records Blast Cell Blood specimen Body Weight Bromodomain CCAAT-Enhancer-Binding Proteins Caliber Calories Carbon Cardiovascular Models Categories Cell Line Cell Nucleus Cells Characteristics Charge Child Childhood Choline Chromatin Chromatin Structure Chronic Circadian Rhythms Classification Climate Clinical Clinical Medicine Cloning Complement Complex Condition Conflict (Psychology)Consumption Control Animal County Coupled CpG dinucleotide Curiosities Custom Cytoplasmic Organelle Cytosine DEXA DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA biosynthesis Data Databases Dedications Densitometry Depth Desire for food Detection Development Diabetes Mellitus Diet Discipline Disease Doctor of Philosophy Dyslipidemias Elements Elevation Embryonic Development End Point Endocrinology Enrollment Ensure Environment Enzymes Epidemic Epigenetic Process Eukaryota Eukaryotic Cell Event Exposure to Family Fasting Fat-Restricted Diet Fatty Liver Fatty acid glycerol esters Female Fetal Development Fetal Growth Retardation Fetal Liver Fetal Weight Fetus Figs - dietary Folate Folic Acid Formaldehyde Funding GPT2 gene Gel Gene Expression Gene Expression Regulation Gene Silencing Generations Genes Genetic Genome Genomic Imprinting Genomics Gluconeogenesis Glucose Glucose Clamp Glycerol Growth HDAC1 gene Health Heat-Shock Proteins 90 Hepatic Hepatic Tissue Hepatitis Heredity Higher Order Chromatin Structure Histologic Histone Acetylation Histone Code Histone Deacetylase Histone H3 Histones Homeostasis Hour Housing Human Hyperinsulinism Hypermethylation Hypothalamic structure Idaho Immunohistochemistry Impairment In Vitro Individual Infant Inflammation Inflammatory Response Institution Insulin Insulin Resistance Intergenic Sequence Intervention Intuition Investigation Japanese Population Kidney Knowledge Laboratories Lactation Language Lead Left Leptin Life Ligation Link Lipid Peroxidation Lipids Liquid Chromatography Literature Liver Lysine MAP Kinase Gene MAPK14 gene MAPK8 gene MTHFR gene Macaca Maintenance Malignant Neoplasms Malnutrition Mammalian Cell Mammals Maps Martens Measures Mediating Medical Medicine Memory Mentors Messenger RNA Metabolic Metabolic Diseases Metabolism Methionine Methods Methylation Methylenetetrahydrofolate reductase (NADPH)Microarray Analysis Mobile Genetic Elements Modeling Modification Molecular Molecular Chaperones Molecular Profiling Mono-S Morbidity - disease rate Mothers Mus Muscle Mutation NF-kappa B Nature Neonatal Neurosecretory Systems Nitric Oxide Pathway Nonesterified Fatty Acids Nuclear Extract Nucleic Acid Regulatory Sequences Nucleosomes Nucleotides Numbers Nutrient Nutritional Obesity Oral Outcome Outcome Study Overweight Oxidative Stress Oxidoreductase Paper Parents Particulate Partner in relationship Pathway interactions Patient currently pregnant Pattern Perinatal Perinatal Exposure Peripheral Peroxisome Proliferator-Activated Receptors Phenotype Phosphorylation Physiological Play Polycomb Polymerase Chain Reaction Population Population Database Positioning Attribute Post-Translational Protein Processing Predisposition Pregnancy Pregnancy Interval Preparation Prevalence Prevention Primates Process Prosencephalon Proteins Public Health Purpose RNA Interference Rate Rattus Reaction Recontacts Records Recruitment Activity Regulation Relative (related person)Research Research Design Research Ethics Committees Research Personnel Research Project Summaries Resolution Resources Retinol dehydrogenase Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Rodent Rodent Model Role Rosa Running Rural Sampling Satiation Scanning Science Series Serum Serum Markers Site Sodium Chloride Specificity Specimen Staining method Stains Standards of Weights and Measures Statistically Significant Structure Subarachnoid Hemorrhage Sum Supplementation System Tail Techniques Testing Tetrahydrofolates Text Therapeutic Thinking Time Tissue-Specific Gene Expression Tissues Tracer Training Transcription factor genes Transgenes Transgenic Organisms Translating Translational Research Trichostatin A Triglycerides Ubiquitination Umbilical Cord Blood Universities Urea Ursidae Family Utah Valproic Acid Variant Vertebral column Very low density lipoprotein Vital Statistics Vitamin B 12 Weaning Weight Gain Western Blotting Woman Work Writing X Inactivation Yeasts Zinc abstracting base bisulfite blood glucose regulation chromatin immunoprecipitation chromatin remodeling circadian pacemaker cofactor cohort comparative data modeling day demethylation density design developmental nutrition dietary supplements epigenomics experience falls feeding fetal gene repression glucose disposal glucose output glucose tolerance health economics high throughput technology human FRAP1 protein human GPT2 protein in utero in vivo in vivo Model inhibitor/antagonist innovation interest juvenile animal lipid transport mRNA Differential Displays mRNA Expression male mature animal metabolomics methionine methyl ester methyl group migration non-alcoholic non-alcoholic fatty liver nonhuman primate novel oil red O oxidation paralogous gene perinatal health postnatal prevent programs promoter research study response sensor sham surgery social success time interval trait transcription factor transgene expression transmission process very low density lipoprotein triglyceride young adult

项目摘要

Project Summary. Obesity causes substantial social, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Accumulating evidence from our laboratory and others suggests that adult metabolic diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Of interest, we have observed in a rodent transgenerational model of intrauterine growth restriction (IUGR) that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult metabolic disease and is associated with abrogation of reprogrammed gene expression. However, although such established models in rodents demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of maternal diet and resultant obesity on primate fetal biology. We hypothesized that a high fat diet in non-human primates would induce changes in hepatic chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult obesity. Based on our preliminary data, the focus of this proposal is to apply developed high throughput technology (comparative epigenomics and metabolomics) to decipher the primate epigenome and metabolome in the obese maternal environment and then measure the impact of supplementation on the differentially altered epigenome and resultant disease. The novel innovation and significance resides within its potential to provide (1) an expanded understanding of the mechanism through which a maternal high fat diet reprograms primate gene expression and (2) a simple intervention (essential nutrient supplementation with neither diet nor behavioral modification) with tremendous potential impact given the current obesity epidemic and the lack of efficacious therapeutics.

项目摘要。肥胖造成巨大的社会、经济和健康负担。肥胖率是儿童（婴儿到年轻人）的发病率不成比例地上升。这种快速增长不太可能是由于仅环境或遗传。我们实验室和其他实验室积累的证据表明，成人代谢疾病起源于子宫内，并且可能通过基因表达的重新编程而发生染色质结构的表观遗传变化（“组蛋白密码”改变）。有趣的是，我们观察到啮齿类动物子宫内生长受限（IUGR）的跨代模型，饮食中添加必需元素营养素，但其热量含量不变，可以预防成人代谢疾病，并与废除重新编程的基因表达。然而，尽管这种在啮齿类动物中建立的模型证明胎儿组蛋白密码的改变与组蛋白密码的持久性和传递有关产后表型改变，但关于母亲饮食和由此产生的肥胖对灵长类动物的影响知之甚少胎儿生物学。我们假设非人类灵长类动物的高脂肪饮食会引起肝脏功能的变化染色质结构导致胎儿基因表达的改变，这对儿童和儿童的发育至关重要成人肥胖。根据我们的初步数据，该提案的重点是应用已开发的高通量破译灵长类表观基因组和代谢组的技术（比较表观基因组学和代谢组学）在肥胖母亲的环境中，然后测量补充剂对差异的影响表观基因组的改变和由此产生的疾病。新颖的创新和意义在于其潜力提供（1）对母亲高脂肪饮食重新编程的机制的更广泛的理解灵长类动物基因表达和（2）简单的干预（既不饮食也不补充必需营养素）行为改变）鉴于当前肥胖流行和缺乏有效的治疗方法。