Location: Children's Nutrition Research Center2014 Annual Report
The overall goal of our research is to define the nutritional distresses and critical windows of development that alter physical activity (PA); understand the various factors that regulate mammary gland (MG) function in lactating mothers; and contribute to the development of nutritionally enhanced plant foods and assess their impact on human health. Specific objectives of this research include: 1) determine the effects of nutrition during critical window(s) of development on voluntary PA during late adolescence and middle age using mouse models; 2) determine the relative contributions of skeletal muscle mass, composition and contractile properties, exercise capacity, motor coordination, and behavior to the differences in voluntary PA induced by the nutritional perturbations incurred in early life; 3) determine the changes in gene and protein expression in skeletal and cardiac muscle and/or brain that contribute to the PA phenotypes induced by alterations in early life; 5) determine the compositional and molecular/genetic changes related to nutrients and bioactive phytochemicals in diverse bean varieties in response to elevated CO2 concentrations, intermittent drought and restricted potassium supply; 6) identify new genes required for calcium oxalate formation in Medicago truncatula; 7) identify genes required for calcium oxalate formation in Glycine max (soybean) and modify calcium oxalate content in Glycine max; 8) determine if microRNAs with plant-associated end chemistry can be functionally incorporated into a mammalian RNA-induced silencing complex/miRNA Ribonuclear Particle; 9) establish that food-associated microRNAs are present and functional in sera and tissues, and establish the relationship between dietary microRNA intake and metabolic changes; 10) determine the pathophysiology of lactation failure in obese women, including the role of progesterone, prolactin, and oxytocin in lactation in obese, as compared to normal weight women; 11) determine the importance of macrophage-mineralocorticoid receptor interaction to mammary gland development; and 12) determine in obese and non-obese lactating women, the relationship between obesity, and maternal oxytocin response during lactation, and breastfeeding success; we will also test whether maternal oxytocin response is positively associated with mother-infant sensitivity and brain reward response to infant face and cry cues using functional magnetic resonance imaging.
These research studies will use various techniques to accomplish the research to be undertaken. Complex and coordinated studies will be performed in mouse models to define the nutritional perturbations (over- and under-nutrition) and critical windows of development (pre- vs. postnatal) that alter physical activity in adulthood; define the type of activity that is altered; and elucidate the physiological basis for the observed changes. Obese and non-obese recent mothers will be recruited, studied, and recorded to evaluate hormone responses to breastfeeding, particularly to evaluate prolactin secretion and progesterone levels as well as oxytocin response variables. MRI scans will be used to evaluate the activation of dopamine-associated brain reward regions in response to seeing own vs. unknown infant face cues. Additionally mice will be utilized to determine if ablation of macrophages during late pregnancy in obese mice will restore milk production and allow for the support of normal weight gain in cross-fostered litters; and we will attempt to understand how stem and progenitor cells are affected by obesity that lead to alterted lactation capacity. To ensure an optimal food supply in the future, work will focus on characterizing how elevated CO2, intermittent drought, or a restricted supply of potassium may impact concentrations of certain minerals, protein, and bioactive phytochemicals in seed or edible vegetative plant tissues. Genome-wide association analysis will be employed to identify genomic loci associated with altered nutritional traits. We will also identify the plant genes that synthesize oxalate and calcium oxalate, and this information will be used to design strategies to manipulate oxalate content in important food plants (such as soybean) for the purpose of improving nutritional quality. Finally, experiments will be conducted to determine whether food-associated plant microRNAs are present and functional in sera and tissues, and to establish the relationship between dietary microRNA intake and metabolic changes.
Project #1. In April, we began the animal breeding with the various dietary manipulations of the pregnant and lactating dams and their offspring that is necessary to conduct the studies described in Objectives 1 and Objective 2. The offspring are now being held until they reach the ages specified (7 and 52 weeks of age) when the various measures of physical activity, cardiovascular fitness, and behavior will be performed. These are planned for the coming months. Project #2. As part of our project, studies have been initiated to assess whole-plant nutrient dynamics in a diverse set of bean cultivars. This will provide the necessary data for subsequent potassium limitation studies, to determine the impact of restricted potassium supply on plant growth, yield, and seed nutritional quality. Experimental procedures are also being developed to effectively manipulate plant water status as a means to understand climate-change related drought effects on bean productivity. For another part of our project, we are working to understand the biochemistry and gene regulation of calcium oxalate formation in plants. Candidate genes required for calcium oxalate crystal formation have been identified utilizing co-expression analysis in the model legume Medicago truncatula. Comparative gene sequence analyses have also been conducted to identify candidate genes in soybean. This will facilitate continued work with this agronomic legume. In the third component of our project, work has been initiated to identify conditions whereby diet-derived nucleic acids are absorbed and potentially function within the consumer, in order to establish guidelines for international food security initiatives, to transform our understanding of the relationship between disease and diet, and to enhance therapeutic potential from plant-based foods. Our preliminary work suggests that individuals with disease-, diet-, or substance-related alterations in intestinal permeability appear to be more likely to absorb dietary microRNAs. Our working model further suggests that impaired kidney function can impede clearance of exogenous microRNAs from circulation. Our initial findings may explain why there is such variability in dietary microRNAs among serum pools derived from multiple consumers, and suggest that individuals with both gut and kidney impairments could be good candidates for exhibiting measurable levels of circulating dietary microRNAs. More work is needed to ascertain the mechanisms for dietary microRNA absorption, and we posit that when optimal conditions are identified, studies can be initiated using relevant microRNAs at physiological concentrations. Planning is underway for further work on the functionality of dietary microRNAs, in which populations with malabsorption phenotypes and glomerular filtration impairments will be analyzed.