In utero exposure to diabetes and future cardiometabolic risk: the role of miRNA

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Abstract The candidate, Jeanie B. Tryggestad, MD, proposes a Mentored Patient-Oriented Research Career Development Award project as a mechanism by which to achieve her ultimate career goal of becoming a physician scientist studying type 2 diabetes and its comorbidities in children, specifically the cardiometabolic effects that emerge in childhood before overt disease. Perinatal conditions like diabetes mellitus (DM) have been shown to “program” offspring for certain metabolic phenotypes later in life. For example, children born to diabetic mothers have been shown to have increased adiposity at birth that can persist through childhood and increase the risk of cardiovascular disease and type 2 diabetes (T2DM) in early adulthood. The mechanisms underpinning this sequence are not well understood, but epigenetic modification has come to the forefront as a potential mediator of the association between perinatal conditions and future cardiometabolic disease. Dr. Tryggestad postulates that altered miRNA expression is an important mechanism by which maternal DM elicits changes that influence cardiometabolic health in the children. She hypothesizes that the diabetic milieu induces changes in fetal endothelial cell miRNA that target specific mRNAs within the endothelial cell and result in miRNA release into the circulation, allowing the miRNA to act on distant tissues. This hypothesis will be tested with the following specific aims: 1) to determine the mechanisms of action of miRNAs 148a and 126 in HUVEC and 2) to examine the abundance of miRNAs 148a and 126 in vivo and in vitro and their impact on distant cells. She will identify target proteins of two miRNAs that are upregulated in endothelial cells of infants of diabetic mothers and assess the impact of these miRNAs on endothelial function. The effect of the miRNAs on distant tissues will also be studied. In the long term, the findings will provide an understanding of the molecular and cellular processes that are altered by the diabetic milieu and result in cardiometabolic complications, including obesity and diabetes, in the offspring of women with diabetes. Further, this work may help us to develop new prevention and treatment strategies. Dr. Tryggestad has demonstrated a commitment to improving children's health through her research in childhood obesity and diabetes. Her research has focused on the cardiometabolic effects of obesity and diabetes on children. Her previous work, funded by Endocrine Fellows Foundation, Pediatric Endocrine Society, and Oklahoma Shared Clinical and Translational Resources Pilot Grant, has resulted in five first- author papers. Dr. Tryggestad is presently an assistant professor at the University of Oklahoma Health Sciences Center in the Department of Pediatrics, Section of Diabetes/Endocrinology. This proposal expands Dr. Tryggestad's research in the cardiometabolic effects of obesity and diabetes. However, training gaps have been identified regarding an in-depth knowledge and understanding of molecular and cellular biology and a lack of understanding of advanced data analysis principles. To reach her goal of independence as a physician scientist, the identified knowledge gaps must be addressed. The K23 award provides a way to meet these gaps. To address the identified gaps, Dr. Tryggestad will: 1) Expand her understanding of miRNA molecular and cellular biology as it specifically relates to diabetes and cardiometabolic disease. This will be accomplished through didactic course work and direct laboratory training in molecular biology techniques by Dr. Jian-Xing Ma in his, and attendance at symposia focused on miRNA and diabetes research. 2) Acquire advanced training in statistical analysis through three additional statistics courses offered through the Department of Biostatistics and Epidemiology in the College of Public Health at the University of Oklahoma Health Sciences Center. In addition, Dr. David Thompson will serve on her mentoring committee and provide statistical oversight for the project, providing additional instruction in statistical analysis. It has been shown that maternal diabetes impacts future cardiometabolic health in offspring, but few studies have sought to understand which factors, when altered by a diabetic milieu, predict worse cardiometabolic outcomes in children. The overall goal is to develop the skills necessary to become an independent researcher devoted to translational research focused on understanding the molecular and cellular processes that are altered by the diabetic milieu and result in cardiometabolic complications, including obesity and diabetes, in the offspring of women with diabetes, and developing new prevention and treatment strategies. The environment at the University of Oklahoma Health Science Center is rich in resources, including opportunities for collaboration. The training in molecular and cellular biology, along with an increased understanding of the principles guiding data analysis, will prepare Dr. Tryggestad to secure future extramural funding and make sound contributions to the field of pediatric endocrinology.