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

• 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
• 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

 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.