Metabolic risk factors for vascular disease throughout the lifespan

整个生命周期中血管疾病的代谢危险因素

• 批准号: 9265483
• 负责人: Jennifer Anne Thompson
• 金额: $ 6.7万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265483
• 关键词: Address; Adult; Area; Award; Birth; Blood Glucose; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic Disease; Clinical Research; Comorbidity; Data; Development; Disease susceptibility; Endothelium; Environment; Enzymes; Epidemic; Event; Experimental Models; Exposure to; Female; Foundations; Functional disorder; Funding; Future; GDF8 gene; Genes; Genetic; Gestational Diabetes; Glucose Intolerance; Goals; Gold; Grant; Growth; Health; Heterogeneity; Hyperglycemia; Hyperinsulinism; Hypertension; Hypertriglyceridemia; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Investigation; Laboratories; Lead; Life; Link; Longevity; Measures; Mentors; Metabolic; Metabolic syndrome; Microvascular Dysfunction; Modeling; Modification; Molecular; Mus; Muscle; Myography; NADP; Obesity; Outcome; Oxidants; Oxidation-Reduction; Paper; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Physiology; Pregnancy; Pregnancy Complications; Publishing; Reactive Oxygen Species; Research; Research Personnel; Residual state; Resolution; Risk; Risk Assessment; Risk Factors; Role; Scientist; Signal Transduction; Stimulus; Technical Expertise; Techniques; Telemetry; Testing; Therapeutic; Thinness; Time; Training; Transgenic Mice; United States National Institutes of Health; Vascular Diseases; Vasodilation; Western World; blood glucose regulation; blood lipid; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; career; clinically relevant; db/db mouse; disorder risk; endothelial dysfunction; fetal; fetal programming; field study; glucose tolerance; improved; insight; maternal obesity; mouse model; multidisciplinary; muscle form; new therapeutic target; novel; offspring; postnatal; prevent; programs; public health relevance; response; vascular abnormality

 DESCRIPTION (provided by applicant): This is a first submission to the NIH Pathway to Independence (K99/R00). Dr. Thompson is establishing herself as an independent investigator in the field of fetal programming, with a particular emphasis on maternal metabolic dysfunction and vascular risk in the offspring. This grant will be critical to achieve the following short and long-term objectives: 1) to acquire additional training in technical skills and scientific knowledg, particularly with respect to vascular function and signaling; 2) to develop an independent project using a model of gestational diabetes that will be serve as a foundation for an independent research program, and 3) to become an independently funded scientist at the forefront of cardiovascular programming. Dr. Thompson has assembled a multidisciplinary team, including mentor, co-mentor and consultants that will guide her career towards independence and assist with the completion of the research proposed in this application. By the end of the funding period of this K99/R00 award, it is expected that Dr. Thompson will have published several high- impact first and last author papers and successfully competed for subsequent NIH funding. The overall objective of the research plan is to explore the impact of metabolic dysfunction on cardiovascular risk throughout the lifespan. In the K99 phase, Dr. Thompson will utilize a dual transgenic mouse model whereby db/db mice are interbred with mice lacking the NADPH enzyme, Nox1, in order to isolate the role of Nox1 in the development of microvascular dysfunction in the context of the metabolic syndrome. Briefly, using gold-standard techniques such as myography and telemetry, cardiovascular function will be measured in db/db and lean mice with and without Nox1 deletion. This mentored project will furnish Dr. Thompson with conceptual and technical skills that will supplement her doctoral training in fetal physiology, and facilitate her independent investigation into the relationship between vascular disease and metabolic complications of pregnancy. In the R00 phase, Dr. Thompson will characterize the cardiometabolic phenotype of offspring born to Hetdb female mice, a novel model of GDM. With use of the same gold-standard techniques proposed for the K99 studies, Dr. Thompson will measure cardiovascular function in offspring born from hyperglycemic or normal pregnancy, with or without a secondary postnatal insult. In order to determine if programmed phenotypic changes trace to the intrauterine hyperglycemic environment, responses to inflammatory/redox stimuli will be measured in vascular cells isolated at term and at various postnatal time-points. This project will set the stage for future investigation into molecular mechanisms linking hyperglycemic pregnancy to abnormal vascular phenotype and allow Dr. Thompson to lay claim to this important field of study.

 描述（由申请人提供）：这是首次提交给NIH独立途径（K99/R 00）。汤普森博士正在建立自己作为一个独立的研究人员在胎儿编程领域，特别强调母亲的代谢功能障碍和血管风险的后代。这笔赠款对于实现以下短期和长期目标至关重要：1）获得技术技能和科学知识方面的额外培训，特别是关于血管功能和信号的培训; 2）使用妊娠糖尿病模型开发一个独立的项目，该项目将作为独立研究计划的基础，和3）成为一个独立资助的科学家在心血管编程的前沿。汤普森已经组建了一个多学科团队，包括导师，共同导师和顾问，将指导她的职业生涯走向独立，并协助完成本申请中提出的研究。到本次K99/R 00奖的资助期结束时，预计汤普森博士将发表数篇高影响力的第一作者和最后作者论文，并成功竞争后续NIH资助。研究计划的总体目标是探索代谢功能障碍对整个生命周期心血管风险的影响。在K99阶段，Thompson博士将利用双转基因小鼠模型，其中db/db小鼠与缺乏NADPH酶Nox 1的小鼠杂交，以分离Nox 1在代谢综合征背景下微血管功能障碍发展中的作用。简而言之，使用金标准技术，如肌描记术和遥测术，将在存在和不存在Nox 1缺失的db/db和瘦小鼠中测量心血管功能。这个指导项目将为汤普森博士提供概念和技术技能，这将补充她在胎儿生理学方面的博士培训， 促进她对血管疾病和妊娠代谢并发症之间关系的独立调查。在R 00阶段，Thompson博士将描述Hetdb雌性小鼠（一种新型GDM模型）所生后代的心脏代谢表型。通过使用K99研究提出的相同金标准技术，Thompson博士将测量高血糖或正常妊娠所生后代的心血管功能，无论是否有二次产后损伤。为了确定程序性表型变化是否可追溯至子宫内高血糖环境，将在足月和出生后不同时间点分离的血管细胞中测量对炎症/氧化还原刺激的反应。该项目将为未来研究高血糖妊娠与异常血管表型相关的分子机制奠定基础，并允许Thompson博士对这一重要研究领域提出要求。

项目成果

Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction.

• DOI: 10.1152/ajpendo.00229.2021
• 发表时间: 2021-11-01
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Mikolajczak A;Sallam NA;Singh RD;Scheidl TB;Walsh EJ;Larion S;Huang C;Thompson JA
• 通讯作者: Thompson JA