Early Life Fatty Acid Exposures Dictate Obesity Predisposition

项目概要和摘要 此应用程序是K 01职业发展奖的重新提交由博士指导。 并由科罗拉多大学安舒茨医学院的雅各布·弗里德曼博士共同指导。 药这项建议的重点是阐明出生后脂肪酸营养建立的机制， 控制新生儿的脂肪发育。研究设计分离了产后营养（牛奶 脂肪酸），而年轻人的牛奶n-6/n-3 PUFA比例暴露将是 使用良好表征的转基因小鼠，结合基本的交叉培养方法进行操作。我 总体假设是，出生后暴露于高n-6/n-3 PUFA使 脂肪形成途径，持续到成年，赋予脂肪细胞内源性肥胖 易感性降低出生后乳汁中PUFA的比例将逆转出生后的编程， 代谢健康的影响。我已经把我的综合训练计划和两本小说结合起来了。 旨在测试出生后母乳PUFA比例对新生儿脂肪发育的特定影响的方法 功能： 出生后乳汁中n-6/n-3 PUFA含量与脂肪前体细胞DNA甲基化水平的关系 AIM 1.确定出生后饮食PUFA比例对大鼠成脂潜力的影响， 脂肪细胞前体细胞 目标2.确定新生儿饮食PUFA改变如何影响脂肪组织发育， 功能 我将通过增加有针对性的教学和技术技能发展，包括高- 通量测序分析，NIDDK示踪剂研讨会，脂肪细胞生物学研讨会，以及技能 流式细胞术、DNA甲基化、同位素示踪剂和代谢表型分析。我招募了一队 在脂肪生物学和儿童肥胖研究领域的高产领导者，包括我的导师， 博士麦克莱恩和共同导师弗里德曼博士，脂肪细胞前体生物学（Klemm和Rodeheffer博士）， 表观遗传学和计算生物学（杨和琼斯博士），以及同位素和脂质的质谱分析 (Dr. Murphy）。这个培训计划包括尖端的表观遗传分析工具，一个杰出的网络， 具有相当专业知识的顾问，以及一种创新的实验方法， 过渡到一个独立的职业生涯作为一个学术科学家在肥胖的发展起源。

Project Summary and Abstract This application is a resubmission for the K01 Career Development Award mentored by Dr. Paul MacLean and co-mentored by Dr. Jacob Friedman at the University of Colorado Anschutz Medical Campus School of Medicine. This proposal focuses on elucidating mechanisms established by postnatal fatty acid nutrition that control adipose development in the neonate. The study design uncouples effects of postnatal nutrition (milk fatty acids) from fetal fatty acid exposures, and the milk n-6/n-3 PUFA ratio exposures in the young will be manipulated using a well-characterized transgenic mouse, combined with a basic cross-fostering approach. My overarching hypothesis is that postnatal exposure to high n-6/n-3 PUFA hypomethylates DNA of adipogenic pathways, which persists into adulthood to confer adipocyte-intrinsic obesity predisposition. Lowering the postnatal milk PUFA ratio will reverse postnatal programming, improving metabolic health later in life. I have integrated my comprehensive training plan with the two novel approaches designed to test specific effects of postnatal milk PUFA ratio on neonatal adipose development and function: Postnatal milk n-6/n-3 PUFA ∆ % DNA methylation in Adipocyte Precursors ∆ Adipose Function AIM1. Determine the effect of postnatal dietary PUFA ratio on the adipogenic potential of adipocyte precursor cells. AIM2. Determine how altered neonatal dietary PUFA affects adipose tissue development and function. I will address gaps in my training by adding targeted didactic and technical skills development, including high- throughput sequencing analysis, NIDDK tracers workshop, and adipocyte biology workshops, as well as skills with flow cytometry, DNA methylation, isotope tracers, and metabolic phenotyping. I have recruited a team of highly productive leaders in the fields of adipose biology and pediatric obesity research, including my mentor Dr. MacLean and co-mentor Dr. Friedman, adipocyte precursor biology (Drs. Klemm and Rodeheffer), epigenetics and computational biology (Drs. Yang and Jones), and in mass spectrometry of isotopes and lipid (Dr. Murphy). This training plan encompasses cutting edge epigenetic analytical tools, an outstanding network of advisors with considerably expertise, and an innovative experimental approach that facilitate a successful transition to an independent career as an academic scientist in the developmental origins of obesity.