Location: Children's Nutrition Research Center
Project Number: 3092-10700-070-002-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2024
End Date: Mar 31, 2029
Objective:
Objective 1: Determine the impact of a maternal high-fat diet on the development of thermogenic adipocytes in the offspring.
Objective 2: Define how early-life transient overexpression of gap junction protein Connexin43 slows fat accretion when mice are fed a high-fat diet.
Sub-objective 2A: Determine whether early-life transient overexpression of gap junction protein Connexin43 improves glucose and lipid homeostasis when mice are fed a high-fat diet.
Sub-objective 2B: Determine whether early-life transient overexpression of gap junction protein Connexin43 alters adipocyte DNA methylation pattern to reprogram adipocyte gene expression.
Objective 3: Define the critical window when gut microbial exposure shapes the epigenetic regulation of intestinal stem cell function.
Sub-objective 3A: Characterize epigenomic changes of intestinal stem cells in response to gut microbial exposures at three age groups equivalent to childhood, adolescence, and adulthood.
Subobjective 3B: Determine the functional roles of microbiota-directed intestinal stem cell epigenetic pathways using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic gene editing and ex vivo organoid assays.
Objective 4: Determine the impact of perinatal nutrition and exercise on cardiovascular development and health.
Sub-objective 4A: Determine if endurance exercise during adolescence produces sustained restoration of LV volume and function in mice undernourished during the terminal phase of heart maturation.
Sub-objective 4B: Determine the cellular and molecular mechanisms responsible for differences in the response of cardiac mass and function to exercise training in postnatal undernutrition mice, and how these are affected by age and sex.
Approach:
The ontogenic periods, when developmentally programmed control of gene expression is being established, are vulnerable to environmental influences, causing life-long functional consequences. Accumulating epidemiologic studies have demonstrated associations between early-life environment and an increased risk for common adult diseases such as obesity, cardiovascular (CV) diseases, and cancer. A challenge is to identify critical windows during which nutrition and other environmental stimuli have the strongest impact on disease risk. This project will elucidate the developmental origins of health and disease. We will use mouse models to study the direct contribution of maternal high-fat diet to the development of thermogenic adipocytes in offspring and identify the underlying transcriptional regulators. We will investigate how a gap junction protein Connexin43 affects the gene expression by epigenetic mechanisms and whether an early-life intervention on adipocytes can reprogram fat deposition, energy balance, and glucose and lipid metabolism in adulthood. We will utilize germ-free mice and gut microbiota transplant experiments to delineate epigenetic cross-talks between gut microbiome and intestinal stem cells at distinct developmental stages. We will also use mouse models to understand the relationship between diet in early life and the risk for developing cardiovascular dysfunction, and how these differ between sexes. Our multidisciplinary approaches will connect phenotypic effects with molecular, cellular, and physiologic mechanisms; apply state-of-the-science techniques for single-cell transcriptomics, genomics, and epigenomics; and use cutting-edge in vivo lineage tracing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing tools to dissect the casual relationships. An integrated understanding of how diet, gut microbiome, and physical activity during critical periods of development lead to permanent changes in tissue structure, function, and epigenetic regulation throughout life should eventually lead to the design of early-life interventions to improve human health.
