The proposed 5-year career development award is intended to provide the candidate with additional training in three areas: physiology and the clinical aspects of obesity and its complications;state-of-the art molecular techniques and computational methods in epigenomics research;and the relationships between DNA sequence, gene expression and metabolic processes. Experts in each of these areas will participate in the candidate's training program and career development, with clear benchmarks for her successful transition to independence. Additionally, structured coursework is proposed to augment the candidate's practical training. The training environment at Washington University School of Medicine is ideally suited to the project's training goals, and the candidate already regularly interacts with her team of mentors in the context of her research interests in metabolic disease and her faculty appointment in the Department of Genetics. The candidate has a solid background in quantitative and comparative genomics and in mouse husbandry and phenotyping, and she has a keen focus on disease mechanism. The research strategy is designed to dissect the relative contributions of genetic and epigenetic effects on dietary obesity-related traits. The study will utilize an established mouse model of metabolic disorders known to have variable responses to dietary fat intake, and will evaluate methylation and gene expression profiles in multiple metabolically relevant tissues in animals phenotyped for obesity-related traits. The genotype-to-phenotype relationship is convoluted. Patterns identified and formalized in a mouse model may have predictive power that is directly translatable to human studies for correlated traits. Once target genes have been validated in mice, the candidate will conduct a pilot study using appropriate human data to address this possibility. This is a first ste towards personalized medicine, and for understanding DNA sequence-metabolic function relationships that are necessary to advance the field and address public health issues. This career development training program will prepare the candidate for a modern and vibrant biomedical research career focused on translating discovery research to clinically relevant metabolic endpoints.
Obesity is an important risk factor for type-2 diabetes and both genetic and epigenetic factors contribute to obesity-related complications. The convoluted genotype-phenotype connection stands in the way of understanding DNA sequence-metabolic function relationships. I propose to dissect variation in methylation and gene expression profiles into their genetic and epigenetic components and explicitly account for factors such as tissue, parent-of-origin, and diet, and compare the effects of these factors among obesity-related phenotypes in mice. Results from this study are directly translatable to human studies and may lead to personalized preventative and/or therapeutic measures based on genetic/epigenetic signatures.
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