Human Mesenchymal Stem Cells and the Epigenetic Programming of Obesity

 描述(申请人提供)：背景：妊娠期肥胖日益被认为是下一代肥胖风险的重要因素。然而，令人惊讶的是，人们对母亲肥胖如何影响人类婴儿的肥胖风险知之甚少。我正在使用从新生儿脐带组织中提取的原代人类间充质干细胞(MSCs)来研究与母亲身体大小相关的宫内暴露如何导致她的婴儿肥胖风险增加。具体来说，我会 研究宫内暴露是否会改变这些脐带细胞的表观遗传学，以确定母亲的肥胖是否会导致婴儿代谢紊乱。表观遗传学是指DNA结构和功能的化学变化，如DNA甲基化，这些变化可能会对基因表达变化和随后的细胞生理产生长期影响。候选人：我是科罗拉多大学医学院儿科的助理教授。我目前得到了NIH K12机构奖的支持，并正在寻求在我剩余的3年培训计划中过渡到个人K01奖。这包括关于DNA甲基化测量的表观遗传学的高级培训，以及用于解释DNA甲基化阵列和RNA测序数据集的大数据集生物统计分析。通过这个培训项目培养的技能对我的长期职业目标将是非常宝贵的，我的长期职业目标是了解怀孕期间肥胖如何影响婴儿肥胖的风险。环境：科罗拉多大学医学院是肥胖症和胎儿程序化研究的绝佳环境。我组建了一支由资深科学家组成的杰出团队，他们在胎儿编程(导师雅各布·弗里德曼博士)、表观遗传学(共同导师伊万娜·杨博士)和生物统计学(共同导师凯特琳娜·凯奇里斯博士)方面具有优势。研究：基于我的初步数据，建立了脐带间充质干细胞模型的可行性，我假设怀孕期间暴露于肥胖会改变这些细胞如何专门化不同类型的细胞(例如，脂肪或肌肉)，以及当这些细胞变成肌肉时 细胞，导致表观遗传修饰导致炎症和胰岛素抵抗。为了解决这些假设，我将使用来自正常体重和肥胖母亲的婴儿的MSCs，以及相应的DNA甲基化阵列和基因表达数据集(RNA测序)来确定母亲肥胖是否会导致后代MSCs的表观遗传修饰，从而影响1)向脂肪或肌肉细胞分化，2)肌肉细胞炎症途径，3)肌肉细胞胰岛素抵抗。识别在功能上与MSC生理学相关的特定表观遗传修饰将使人们对 肥胖的胎儿程序化。

 DESCRIPTION (provided by applicant): Background: Obesity during pregnancy is increasingly recognized as an important contributor to obesity risk in the next generation. However, surprisingly little is known about how maternal obesity influences obesity risk for human babies. I am using primary, human mesenchymal stem cells (MSCs) derived from umbilical cord tissue of newborn babies to investigate how intrauterine exposures associated with mother's body size may contribute to increased obesity risk for her baby. Specifically, I will investigate whether intrauterine exposures alter the epigenetics of these umbilical cord cells to determine whether mothers' obesity contributes to disordered metabolism in her baby. Epigenetics refers to chemical changes in the DNA structure and function, such as DNA methylation, that can have long-term consequences for altered gene expression and subsequent cellular physiology. Candidate: I am an Assistant Professor in the Department of Pediatrics, at the University of Colorado School of Medicine. I am currently supported by an institutional NIH K12 award and am seeking to transition to an individual K01 award for the remaining 3 years of my training program. This includes advanced training in epigenetic bench science for the measurement of DNA methylation and large dataset biostatistical analyses for the interpretation of DNA methylation array and RNA sequencing datasets. The skills developed through this training program will be invaluable to my long-term career goal of understanding how obesity during pregnancy impacts the baby's risk for becoming obese. Environment: The University of Colorado School of Medicine is an excellent environment for obesity and fetal programming research. I have put together an exceptional team of senior scientists with strengths in fetal programming (Mentor Jacob Friedman, PhD), as well as epigenetics (Co-Mentor Ivana Yang, PhD) and biostatistics (Co-Mentor Katerina Kechris, PhD). Research: Based on my preliminary data, which establish the feasibility of the umbilical cord MSC model, I hypothesize that exposure to obesity during pregnancy alters how these cells become specialized for different cell types (i.e., fat or muscle), and that when these cells become muscle cells, results in epigenetic modifications leading to inflammation and insulin resistance. To address these hypotheses, I will use MSCs from babies of normal weight and obese mothers, along with corresponding DNA methylation array and gene expression datasets (RNA sequencing) to determine whether maternal obesity induces epigenetic modifications in offspring MSCs that subsequently affect 1) differentiation to fat or muscle cells, 2) muscle cell inflammation pathways, and 3) muscle cell insulin resistance. Identifying specific epigenetic modifications that are functionally relevant to MSC physiology will give critical insights into the fetal programming of obesity.