Early Life Fatty Acid Exposures Dictate Obesity Predisposition

项目总结和摘要(如有需要，从原母公司K01结转) 本申请表是对保罗·麦克莱恩博士指导的K01职业发展奖的重新提交 并由科罗拉多大学安舒茨医学院雅各布·弗里德曼博士共同指导 医学。这项建议侧重于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。研究设计不考虑产后营养(牛奶)的影响 脂肪酸)，而乳汁中n-6/n-3多不饱和脂肪酸暴露量的比率将是 使用特征良好的转基因小鼠进行操作，并结合基本的交叉培养方法。我的 最重要的假设是，出生后暴露于高n-6/n-3多不饱和脂肪酸的DNA低甲基化 成脂途径--持续到成年期导致脂肪细胞固有肥胖 性情。降低出生后牛奶多不饱和脂肪酸比率将逆转出生后编程，改善 晚年的新陈代谢健康。我已经将我的全面训练计划与这两本小说结合起来 检测产后牛奶多不饱和脂肪酸比例对新生儿脂肪发育特异性影响的方法 和功能： 乳汁n-6/n-3多不饱和脂肪酸∆%甲基化在脂肪细胞前体∆脂肪功能中的作用 AIM1.测定仔猪日粮多不饱和脂肪酸比例对其成脂潜能的影响 脂肪细胞前体细胞。 AIM2.确定改变的新生儿膳食多不饱和脂肪酸如何影响脂肪组织的发育和 功能。 我将通过增加有针对性的教学和技术技能发展来解决我的培训中的差距，包括高 吞吐量测序分析，NIDDK示踪剂研讨会，脂肪细胞生物学研讨会，以及技能 用流式细胞术、DNA甲基化、同位素示踪剂和代谢表型。我招募了一支团队 脂肪生物学和儿童肥胖研究领域的高生产率领导者，包括我的导师 MacLean博士和共同导师Friedman博士，脂肪细胞前体生物学(Klemm博士和Rodeheffer博士) 表观遗传学和计算生物学(杨和琼斯博士)，以及同位素和脂类的质谱学 (墨菲博士)这项培训计划包括尖端的表观遗传分析工具，一个杰出的网络 拥有相当专业知识的顾问和创新的实验方法，有助于成功 作为一名研究肥胖发展起源的学术科学家，过渡到独立的职业生涯。

Project Summary and Abstract (carried over from original parent K01 if needed) 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.