Early Life Fatty Acid Exposures Dictate Obesity Predisposition

生命早期的脂肪酸暴露决定了肥胖倾向

• 批准号: 10391129
• 负责人: Michael C. Rudolph
• 金额: $ 7.87万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391129
• 关键词: Active Sites; Address; Adipocytes; Adipose tissue; Adult; Affect; Biology; COVID-19; Colorado; Computational Biology; DNA; DNA Methylation; Development; Educational workshop; Epigenetic Process; Exposure to; Fatty Acids; Flow Cytometry; Fostering; Funding; Health; Health Sciences; High-Throughput Nucleotide Sequencing; Indirect Calorimetry; Isotopes; K-Series Research Career Programs; Laboratory Research; Life; Lipids; Mass Spectrum Analysis; Medical; Mentors; Metabolic; Milk; N-3 polyunsaturated fatty acid; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Obesity; Oklahoma; Parents; Pathway interactions; Predisposition; Publications; Research; Research Design; Scientist; Technical Expertise; Testing; Time; Tracer; Training; Transgenic Mice; Universities; Wages; Work; Yang; adipocyte biology; analytical tool; career; design; dietary; fetal; improved; innovation; medical schools; metabolic phenotype; neonate; novel strategies; nutrition; obesity in children; postnatal; precursor cell; programs; recruit; skill acquisition; skills

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.

项目摘要和摘要（如果需要，可从原始父级 K01 继承） 本申请是 Paul MacLean 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 Jacob Friedman 博士共同指导 医学。该提案的重点是阐明产后脂肪酸营养建立的机制。 控制新生儿的脂肪发育该研究设计消除了产后营养（牛奶）的影响。 脂肪酸）来自胎儿脂肪酸暴露，而年轻人的乳汁 n-6/n-3 PUFA 比率暴露将 使用特征明确的转基因小鼠结合基本的交叉培养方法进行操作。 总体假设是出生后接触高 n-6/n-3 PUFA 会使 DNA 低甲基化 脂肪形成途径，持续到成年期，导致脂肪细胞内在肥胖 降低产后乳汁中的 PUFA 比例将逆转产后编程，从而改善。 我将我的综合训练计划与这两本小说结合起来。 旨在测试产后牛奶多不饱和脂肪酸比例对新生儿脂肪发育的具体影响的方法 和功能： 产后乳汁 n-6/n-3 PUFA Δ 脂肪细胞前体中 DNA 甲基化百分比 Δ 脂肪功能 AIM1. 确定产后膳食 PUFA 比例对脂肪形成潜力的影响 脂肪细胞前体细胞。 AIM2. 确定新生儿膳食 PUFA 的改变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弥补培训中的差距，包括高水平 通量测序分析、NIDDK 示踪剂研讨会和脂肪细胞生物学研讨会以及技能 我招募了一个团队，负责流式细胞术、DNA 甲基化、同位素示踪剂和代谢表型分析。 脂肪生物学和儿科肥胖研究领域的高产领导者，包括我的导师 MacLean 博士和联合导师 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（杨博士和琼斯），以及同位素和脂质的质谱分析 （墨菲博士）该培训计划包括尖端的表观遗传分析工具和出色的网络。 具有丰富专业知识的顾问，以及促进成功的创新实验方法 过渡为独立职业，作为肥胖发育起源的学术科学家。

项目成果

Fat-1 Transgene Is Associated With Improved Reproductive Outcomes.

Fat-1 转基因与改善生殖结果相关。

• DOI: 10.1210/en.2018-00723
• 发表时间: 2018-11-06
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: N. Hohos;K. Cho;D. Swindle;A. Allshouse;Michael C. Rudolph;M. Skaznik
• 通讯作者: M. Skaznik

Liver X receptor-α activation enhances cholesterol secretion in lactating mammary epithelium.

肝脏 X 受体-α 激活增强哺乳期乳腺上皮的胆固醇分泌。

• DOI: 10.1152/ajpendo.00548.2018
• 发表时间: 2019-06-01
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Diego Y. Grinman;V. Careaga;E. Wellberg;M. Dansey;Edith C Kordon;S. M. Anderson;Marta S Maier;Ge
• 通讯作者: Ge