Metabolic risk factors for vascular disease throughout the lifespan

 描述(由申请人提供)：这是第一次提交给美国国立卫生研究院独立之路(K99/R00)。汤普森博士正在确立自己在胎儿程序化领域的独立研究人员的地位，尤其关注母体代谢功能障碍和后代的血管风险。这笔赠款将对实现以下短期和长期目标至关重要：1)获得额外的技术技能和科学知识培训，特别是在血管功能和信号方面；2)开发一个使用妊娠期糖尿病模型的独立项目，作为独立研究计划的基础；以及3)成为一名独立资助的心血管规划前沿科学家。汤普森博士已经组建了一个多学科团队，包括导师、共同导师和顾问，他们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K99/R00奖项的资助期结束时，预计汤普森博士将发表几篇高影响力的第一和最后作者论文，并成功竞争随后的NIH资金。该研究计划的总体目标是探索代谢功能障碍对一生中心血管风险的影响。在K99阶段，汤普森博士将利用双重转基因小鼠模型，将db/db小鼠与缺乏NADPH酶Nox1的小鼠杂交，以分离Nox1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，如肌图术和遥测，将测量db/db和Nox1缺失和不缺失的瘦小鼠的心血管功能。这个有指导的项目将为汤普森博士提供概念和技术技能，这些技能将补充她在胎儿生理学方面的博士培训。 协助她对血管疾病和妊娠代谢并发症之间的关系进行独立调查。在R00阶段，汤普森博士将描述Hetdb雌性小鼠所生后代的心脏代谢表型，Hetdb雌性小鼠是GDM的新模型。汤普森博士将使用为K99研究建议的相同金标准技术，测量高血糖或正常怀孕、有或没有二次产后侮辱的后代的心血管功能。为了确定程序性表型变化是否追溯到宫内高血糖环境，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之间的分子机制奠定基础，并使汤普森博士能够进入这一重要研究领域。

 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.