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

子宫内糖尿病暴露和未来心脏代谢风险：miRNA 的作用

• 批准号: 9351499
• 负责人: Jeanie Beatrice Tryggestad
• 金额: $ 15.43万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-12 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351499
• 关键词: 3' Untranslated Regions; Address; Affect; Age; Apoptosis; Binding; Biological Markers; Biometry; Birth; Blood Circulation; Cell physiology; Cells; Child; Child health care; Childhood; Clinical; Collaborations; Comorbidity; Data Analyses; Diabetes Mellitus; Diabetic mother; Dietary Intervention; Disease; Distant; Endocrine; Endocrinology; Endothelial Cells; Endothelin-1; Environment; Epidemiology; Epigenetic Process; Exposure to; Extramural Activities; Foundations; Functional disorder; Funding; Future; Glucose; Goals; Grant; Health; Health Sciences; Human; IGF1 gene; IGF1R gene; IRS1 gene; Immunofluorescence Immunologic; Impairment; In Situ Nick-End Labeling; In Vitro; Infant; Instruction; Insulin; Insulin Signaling Pathway; Knowledge; Life; Luciferases; Measures; Mediating; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentors; Messenger RNA; Metabolic; MicroRNAs; Modification; Molecular; Molecular Biology Techniques; Molecular and Cellular Biology; Mothers; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oklahoma; Organ; Outcome; Paper; Perinatal; Physicians; Play; Prevalence; Prevention strategy; Production; Proteins; Public Health; RNA Binding; RNA Sequences; Reporter; Repression; Research; Research Design; Research Personnel; Resources; Risk; Role; Scientist; Secure; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Societies; Statistical Data Interpretation; Techniques; Testing; Time; Tissues; Training; Translational Research; Translations; Umbilical Cord Blood; Umbilical vein; Universities; Untranslated RNA; Vascular Cell Adhesion Molecule-1; Western Blotting; Woman; Work; Youth; cardiometabolic risk; cardiovascular disorder risk; career; cell growth; college; diabetic; disorder risk; emerging adult; exercise intervention; exosome; fetal; glucose metabolism; improved; in utero; in vivo; infant of diabetic mother; insulin signaling; intercellular cell adhesion molecule; interest; laboratory experience; maternal diabetes; metabolic phenotype; obesity in children; offspring; pediatric department; prenatal; prenatal exposure; prevent; professor; programs; protein expression; skills; sound; statistics; symposium; treatment strategy; vector

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.

抽象的 候选人珍妮·B·特里格斯塔德（Jeanie B. Tryggestad）医学博士提出了以患者为导向的指导性研究职业 发展奖项目作为实现她成为一名最终职业目标的机制 研究 2 型糖尿病及其儿童合并症，特别是心脏代谢疾病的医师科学家 糖尿病 (DM) 等围产期疾病在儿童期出现的影响。 已被证明可以对后代的某些代谢表型进行“编程”，例如，出生的孩子。 患有糖尿病的母亲已被证明在出生时体重增加，并且可以持续整个童年和 增加成年早期患心血管疾病和 2 型糖尿病 (T2DM) 的风险。 这一序列的基础尚不清楚，但表观遗传修饰作为一种 围产期状况与未来心脏代谢疾病之间关联的潜在中介。 Tryggestad 发帖称改变 miRNA 表达是母体 DM 引发的重要机制 影响儿童心脏代谢健康的变化。 诱导胎儿内皮细胞 miRNA 的变化，这些变化针对内皮细胞内的特定 mRNA，并且 导致 miRNA 释放到循环中，从而使 miRNA 作用于远处的组织。 测试的具体目的如下： 1) 确定 miRNA 148a 和 126 的作用机制 在 HUVEC 中，2) 检查体内和体外 miRNA 148a 和 126 的丰度及其对 她将鉴定在婴儿内皮细胞中上调的两种 miRNA 的靶蛋白。 糖尿病母亲的研究并评估这些 miRNA 对内皮功能的影响。 从长远来看，研究结果将提供对远处组织的了解。 糖尿病环境改变的分子和细胞过程并导致心脏代谢 此外，这项工作可能会导致糖尿病女性的后代出现并发症，包括肥胖和糖尿病。 帮助我们制定新的预防和治疗策略。 Tryggestad 博士通过她的研究表明了对改善儿童健康的承诺 她的研究重点是肥胖和糖尿病对心脏代谢的影响。 她之前的工作由内分泌研究员基金会儿科内分泌资助。 协会和俄克拉荷马州共享临床和转化资源试点拨款，已获得五项第一- Tryggestad 博士目前是俄克拉荷马大学健康分校的助理教授。 儿科科学中心糖尿病/内分泌科。 该提案扩展了 Tryggestad 博士在肥胖和糖尿病对心脏代谢影响方面的研究。 然而，在对分子生物学的深入了解和理解方面，已经发现了培训差距。 和细胞生物学以及缺乏对先进数据分析原理的理解来实现她的目标。 作为一名医师科学家的独立性，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，为了解决已发现的差距，Tryggestad 博士将： 1) 扩展她对 miRNA 分子和细胞生物学的理解，因为它与糖尿病和 这将通过教学课程和直接实验室培训来完成。 马建兴博士在他的分子生物学技术领域获得博士学位，并参加了以 miRNA 为主题的研讨会 和糖尿病研究。 2) 通过以下机构提供的三门额外的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 此外，大卫·汤普森博士将在她的指导委员会中任职并提供帮助。 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，但研究很少 试图了解哪些因素在被糖尿病环境改变时会预测更差的心脏代谢 总体目标是培养成为独立研究人员所需的技能。 致力于转化研究，重点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 患有糖尿病的妇女的后代，并制定新的预防和治疗策略。 俄克拉荷马大学健康科学中心拥有丰富的资源，包括 分子和细胞生物学方面的合作，以及对分子和细胞生物学的更多了解。 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并做出 为儿科内分泌学领域做出了积极贡献。