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

摘要 候选人珍妮B。Tryggestad博士提出了一个以患者为导向的指导研究生涯 发展奖项目作为一种机制，通过它来实现她的最终职业目标， 研究2型糖尿病及其儿童合并症的医生科学家，特别是心脏代谢 在儿童期出现的症状围产期疾病如糖尿病（DM） 已经被证明可以“编程”后代在以后的生活中的某些代谢表型。例如， 患有糖尿病的母亲在出生时肥胖增加，这种肥胖可以持续到童年， 增加成年早期患心血管疾病和2型糖尿病（T2 DM）的风险。的机制 支撑这一序列的基因还没有很好地理解，但表观遗传修饰已经成为最前沿的一个领域。 围产期条件和未来的心脏代谢疾病之间的关联的潜在介质。博士 Tryggestad假设miRNA表达的改变是母体糖尿病发病的重要机制 影响儿童心脏代谢健康的变化。她假设糖尿病患者的环境 诱导靶向内皮细胞内特异性mRNA的胎儿内皮细胞miRNA的变化， 导致miRNA释放到循环中，允许miRNA作用于远处的组织。这一假设将 1）确定miRNAs 148 a和126的作用机制 2）检测miRNAs 148 a和126在体内和体外的丰度及其对HUVEC的影响。 遥远的细胞她将鉴定两种在婴儿内皮细胞中上调的miRNAs的靶蛋白 并评估这些miRNAs对内皮功能的影响。miRNAs的作用 也将研究远距离组织。从长远来看，研究结果将提供一个了解 分子和细胞过程被糖尿病环境改变并导致心脏代谢 糖尿病女性的后代会出现并发症，包括肥胖和糖尿病。此外，这项工作可以 帮助我们制定新的预防和治疗战略。 Tryggestad博士通过她的研究， 儿童肥胖和糖尿病。她的研究集中在肥胖对心脏代谢的影响， 儿童糖尿病她以前的工作，由内分泌研究员基金会，儿科内分泌 社会，和俄克拉荷马州共享临床和翻译资源试点赠款，已导致五个第一- 作者论文。Tryggestad博士目前是俄克拉荷马州卫生大学的助理教授 儿科科学中心，糖尿病/内分泌科。 这项提议扩展了Tryggestad博士在肥胖和糖尿病对心脏代谢影响方面的研究。 然而，在深入了解和理解分子生物学方面， 和细胞生物学以及缺乏对高级数据分析原理的理解。为了达到她的目标， 作为一名医生和科学家，必须解决已确定的知识差距。K23奖 提供了一种弥补这些差距的方法。为了解决已确定的差距，Tryggestad博士将： 1)扩大她对miRNA分子和细胞生物学的理解，因为它特别涉及糖尿病， 心脏代谢疾病这将通过教学课程工作和直接的实验室培训来完成 马建兴博士在他的分子生物学技术，并出席研讨会集中在miRNA 糖尿病研究。 2)通过下列机构提供的另外三个统计课程，获得统计分析方面的高级培训： 俄克拉荷马州大学公共卫生学院生物统计学和流行病学系 健康科学中心。此外，大卫汤普森博士将担任她的指导委员会，并提供 对项目进行统计监督，提供统计分析方面的额外指导。 研究表明，母亲糖尿病会影响后代未来的心脏代谢健康，但很少有研究表明， 我试图了解哪些因素，当被糖尿病环境改变时，预测心脏代谢更差， 儿童的成果。总体目标是发展成为独立研究人员所需的技能 致力于翻译研究，重点是了解分子和细胞过程， 糖尿病环境改变并导致心脏代谢并发症，包括肥胖和糖尿病， 糖尿病妇女的后代，并制定新的预防和治疗策略。环境 俄克拉荷马州健康科学中心的大学资源丰富，包括 协作在分子和细胞生物学的培训，沿着增加的理解， 指导数据分析的原则，将为Tryggestad博士做好准备，以确保未来的校外资金， 对儿科内分泌学领域的贡献。

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.