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

摘要 候选人Jeanie B.Tryggestad医学博士提出了一种以患者为导向的研究指导生涯 发展奖项目作为一种机制，通过它实现她成为一名 研究儿童2型糖尿病及其合并症，特别是心脏代谢的内科科学家 在儿童时期出现的影响，在明显的疾病之前。像糖尿病(DM)这样的围产期疾病 被证明在以后的生活中为后代的某些新陈代谢表型“编程”。例如，出生在 研究表明，糖尿病母亲在出生时就会增加肥胖症，这种肥胖症可能会持续到童年和 在成年早期增加心血管疾病和2型糖尿病(T2 DM)的风险。其作用机制 支持这一序列的原因还不是很清楚，但表观遗传修饰已经作为一种 围产期疾病和未来心脏代谢性疾病之间关联的潜在中介。Dr。 Tryggestad推测，miRNA表达的改变是母体糖尿病诱发糖尿病的重要机制 影响儿童心脏代谢健康的变化。她假设糖尿病的环境 诱导胎儿内皮细胞miRNA的变化，该miRNA针对内皮细胞内的特定mRNAs和 导致miRNA释放到循环中，使miRNA作用于远处的组织。这一假说将 测试的具体目的如下：1)确定miRNAs 148A和126的作用机制 和2)检测体内和体外miRNAs 148A和126的丰度及其对人脐静脉内皮细胞的影响 遥远的手机。她将确定两个在婴儿内皮细胞中上调的miRNAs的目标蛋白 并评估这些miRNAs对内皮功能的影响。MiRNAs的作用 对远处组织的影响也将被研究。从长远来看，这些发现将提供对 被糖尿病环境改变并导致心脏代谢的分子和细胞过程 糖尿病妇女后代的并发症，包括肥胖和糖尿病。此外，这项工作可能 帮助我们制定新的预防和治疗策略。 Tryggestad博士通过她的研究展示了她对改善儿童健康的承诺 儿童肥胖和糖尿病。她的研究主要集中在肥胖对心脏代谢的影响和 儿童患糖尿病。她之前的工作，由儿科内分泌研究员基金会资助 社会，以及俄克拉荷马州共享临床和转化资源试点赠款，已导致五个第一- 作者论文。Tryggestad博士目前是俄克拉荷马大学健康学院的助理教授 儿科科学中心，糖尿病/内分泌科。 这项建议扩大了Tryggestad博士对肥胖和糖尿病对心脏代谢影响的研究。 然而，在对分子的深入知识和理解方面，已经确定了培训差距 和细胞生物学，缺乏对高级数据分析原理的理解。为了达到她的目标 作为一名内科科学家，必须解决已确定的知识差距。K23大奖 提供了一种弥补这些差距的方法。为了解决已发现的差距，特雷格斯塔德博士将： 1)扩大她对miRNA分子和细胞生物学的理解，因为它特别与糖尿病和 心脏代谢疾病。这将通过授课作业和直接的实验室培训来实现。 在分子生物学技术方面，马建兴博士在他的报告中，出席了以miRNA为重点的研讨会 和糖尿病研究。 2)通过以下方式提供的另外三门统计课程，获得统计分析方面的高级培训 俄克拉荷马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·汤普森博士将在她的指导委员会任职，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。 已有研究表明，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 都试图了解当糖尿病环境改变时，哪些因素会预测心脏代谢的恶化 对儿童的影响。总体目标是培养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 被糖尿病环境改变，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，并开发新的预防和治疗策略。环境问题 在俄克拉荷马大学健康科学中心拥有丰富的资源，包括 协作。分子和细胞生物学方面的培训，以及对 指导数据分析的原则，将使Tryggestad博士做好准备，以确保未来的外部资金和 对儿科内分泌学领域的良好贡献。

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.