Location: Microbiome and Metabolism Research
Project Number: 6026-51000-012-000-D
Project Type: In-House Appropriated
Start Date: Mar 4, 2019
End Date: Mar 3, 2024
Objective:
The overall objective of this project is to gather evidence about important environmental factors that have long-term consequences on child development/health, and their health as children become adults. The following objectives will be sought via five independent research studies:
1: Evaluate the role of epigenomic and postnatal factors in maternal obesity-associated programming of offspring metabolic, skeletal and cardiovascular outcomes. (Proj 1)
2: Determine the role of maternal germ line (oocyte) and placental (trophoblast) innate immune response signaling in mediating developmental programming in offspring. (Proj 1)
3: Determine the role of postnatal nutrition and dietary factors on physiology and metabolism. (Proj 2)
4: Determine if there is a persistent effect of early life nutritional factors on bone and metabolic health. (Proj 2)
5: Define host-microbiome cross-talk and xenometabolism in humans and rodent models relevant to human health. (Proj 2)
6: Examine the effect of maternal obesity, exercise and diet on programming the offspring's metabolism and risk of obesity during the first 8 years of life. (Proj 3)
7: Investigate the role of exercise during gestation in mitigating maternal programming of offspring metabolism. (Proj 3)
8: Test the feasibility and efficacy of peri-conception exercise intervention on mitigating maternal obesity programming. (Proj 3)
9: Determine bioenergetics phenotypes that link exercise to metabolic health in normal weight (NW) and obese (OB) children. (Proj 4)
10: Examine the persistent effects of early-life exercise, and the impact on childhood and adolescent metabolic health. (Proj 4)
11: Examine molecular signals and mechanisms associated with exercise, fatigue and muscle. (Proj 4)
12: Use participants in the Beginnings cohort to determine the effects of early diet on neurocognitive development in healthy children and adolescents. (Proj 5)
13: Evaluate the impact of maternal obesity on brain development and function of offspring in early childhood. (Proj 5)
14: Determine the effects of diet composition, meal pattern, and exercise on brain function and behavioral dynamics important for learning and school performance in lean and obese children. (Proj 5)
15: Determine the role of prenatal factors on mother’s health.
16: Investigate the role of prenatal factors and postnatal factors on infants’ health.
Approach:
Studies will focus on: 1) the risk of obesity and development of key physiological systems are subject to programming at conception and maternal obesity and high-fat diets during pregnancy increase the risk of offspring obesity, and co-morbidities such as cardiovascular disease and non-alcoholic fatty liver disease. We will address specific mechanisms (Ezh2-mediated gene repression) in developmental programming and the role of specific signaling pathways in the placenta and oocyte per se in long-term programming via mouse models. We will examine developmental programming of adipose tissue and energy balance, bone health and osteoblast differentiation, and peri-vascular fat and vasculature, to address programming of weight gain, skeletal health and cardiovascular function. 2) the roles of postnatal and early-life dietary factors and the gut microbiota on host health and development through clinical and animal models to investigate how dietary and microbiome factors impact childhood development, and identify and characterize molecular cross-talk between microbes and the host. 3) clinical studies to investigate how maternal obesity can influence offspring development and health outcomes. We will explore differences in umbilical cord mesenchymal stem cells from infants born to normal weight and obese mothers for adipogenesis potential, lipolysis and mitochondrial bioenergetics. We will identify exercise-specific alterations in maternal gut microbiota during pregnancy as well as the direct effects of exercise on placental inflammation and placental nutrient transfer and its implication for long-term developmental programming in the offspring. 4) determine the impact of early-life physical activity (PA) on muscle and metabolic health, determine modifying effects of PA on energy and substrate metabolism, and determine specific muscle metabolic systems that associate with fitness, PA, fatigue and exertion phenotypes. We will determine bioenergetics phenotypes that reflect PA and obesity status, through studies of mitochondrial function in circulating cells, use of carbohydrates and fat during exercise, and optimal protein needs; focus on metabolic impact of early life PA by establishing the relation between maternal obesity and the child’s PA level, determine feasibility of a PA intervention in at-risk young children, and detail the molecular and metabolic pathways affected by early life PA. 5) measuring gut microbiome associations with immune and metabolic functions, and identify specific microbe-derived metabolites that could play a role. We aim to identify and characterize mechanisms of action of dietary components and gut microbes, which will improve formula diets for the benefit of a child's growth, development and immune function; identify mechanisms by which the gut microbiota influence both short- and long-term health outcomes; enable design of evidence-based interventions to thwart immune, bone and metabolic diseases; and identify microbial and/or host molecular mechanisms that can be targeted by diet or other interventions to prevent metabolic diseases and improve function.
