Human Mesenchymal Stem Cells and the Epigenetic Programming of Obesity

人类间充质干细胞与肥胖的表观遗传编程

基本信息

批准号：
9108960
负责人：
Kristen Elizabeth Boyle
金额：
$ 13.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108960
关键词：
Address Adipocytes Affect Animals Antioxidants Biometry Birth Body Size Cardiovascular Diseases Cell Culture Techniques Cell model Cell physiology Cells Chemicals Child Chronic Disease Clinical Oncology Supplement (K12)Colorado Coronary heart disease DNA Methylation DNA Modification Methylases DNA Structure Data Data Set Diabetes Mellitus Diagnosis Doctor of Philosophy Environment Epidemic Epigenetic Process Exhibits Exposure to Fatty acid glycerol esters GLUT4 gene Gene Expression Glucose Transporter Goals Health Histocompatibility Testing Human Individual Infant Inflammation Inflammatory Insulin Insulin Resistance Life Liver diseases Measurement Mentored Research Scientist Development Award Mentors Mesenchymal Stem Cells Metabolic Diseases Modeling Modification Mothers Muscle Muscle Cells Neonatal Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Overweight Oxidative Stress Oxidative Stress Pathway Pathway interactions Play Pregnancy Research Risk Risk Factors Role Science Senior Scientist Skeletal Muscle TLR4 gene Tissues Training Training Programs Umbilical cord structure United States United States National Institutes of Health Universities Weight Yang base biological adaptation to stress bone career cell type cohort fetal fetal programming glucose uptake glutathione peroxidase GPX1 in utero inflammatory marker insight lifestyle factors lipid biosynthesis medical schools myogenesis neonate next generation non-alcoholic fatty liver novel nutrition obesity risk offspring pediatric department physical inactivity professor programs skills stem cell differentiation transcriptome sequencing

项目摘要

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.

描述（适用提供）：背景：越来越多地认为怀孕期间的肥胖症是下一代肥胖风险的重要促进者。但是，令人惊讶的是，关于孕产妇肥胖如何影响人类婴儿的肥胖风险知之甚少。我正在使用源自新生婴儿的脐带组织的原发性，间充质干细胞（MSC）来研究与母亲体大小相关的内在暴露如何有助于增加婴儿的肥胖风险。具体来说，我会的调查插入式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有助于婴儿的代谢无序。表观遗传学是指DNA结构和功能（例如DNA甲基化）的化学变化，这些变化可能会对基因表达改变和随后的细胞生理学产生长期后果。候选人：我是科罗拉多大学医学院儿科学系的助理教授。目前，我获得了机构NIH K12奖的支持，并正在寻求过渡到我剩下的3年培训计划的单个K01奖。这包括用于测量DNA甲基化和大型数据集生物统计学分析的表观遗传基础科学的高级培训，以解释DNA甲基化阵列和RNA测序数据集。通过此培训计划发展的技能对于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和胎儿编程研究的绝佳环境。我组建了一个高级科学家团队，具有胎儿编程的优势（导师雅各布·弗里德曼（Jacob Friedman），博士学位），以及表观遗传学（同事伊瓦娜·杨（Ivana Yang），博士学位）和BioStatistics（Co-Intoror Katerina Kechris，Phd）。研究：根据我的初步数据，建立了脐带MSC模型的可行性，我假设怀孕期间暴露于肥胖症会改变这些细胞如何专门针对不同的细胞类型（即脂肪或肌肉），并且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。 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 injection pathways, and 3) muscle cell insulin resistance.识别与MSC生理功能相关的特定表观遗传修饰将为您提供关键的见解肥胖的胎儿编程。