PROJECT SUMMARY The development of cardiovascular disease (CVD) is a complex process, with obesity being a major risk factor. Weight loss among overweight/obese individuals is a key component of the primary prevention of CVD, but there is marked variability across individuals in response to lifestyle weight loss interventions. It is critical to improve our understanding of drivers of weight loss responsiveness as this may help identify causal factors in obesity and may ultimately lead to new or more personalized prevention or treatment opportunities. This study will examine how genetics, gut microbiota (GM), and metabolites contribute towards measures of responsiveness during an ongoing 1-year lifestyle weight loss trial of the standard weight loss approach, daily caloric restriction (DCR), versus a novel alternative, intermittent fasting (IMF). This understanding of the causal relationships between omic profiles and weight loss/health improvements in an interventional setting will target an investigation into GM and metabolites as mediators of the association between genetic obesity risk and obesity-related phenotypes in larger epidemiological cohorts. Preliminary data from a participant subset in the intervention that provides evidence of feasibility and informs the hypotheses for the following innovative aims: Aim 1: Assess longitudinal changes in GM and metabolites, as well as the predominant drivers of these changes, during a lifestyle weight loss intervention of DCR versus IMF. Aim 2: Evaluate associations of a measure of genetic risk for obesity and GM/metabolites with responsiveness during a lifestyle weight loss intervention. Aim 3: Investigate whether GM/metabolites mediate the association between a multiethnic obesity polygenic risk score and measures of obesity in two epidemiological cohorts. This Career Development Award will also provide the Candidate with the opportunity to gain important skills and expertise. She has a clear plan to gain training related to: 1) processing shotgun metagenomic GM and metabolomic data; 2) causal inference and other relevant methods for the analysis of multi-omics data; and 3) multiethnic polygenic risk scores. The training plan involves coursework, conference attendance, and in-person training with leading scholars, in conjunction with guidance from a mentorship team of renowned leaders in their respective fields of genetic epidemiology (Dr. Leslie Lange; Primary Mentor), bioinformatics and the human gut microbiome (Dr. Catherine Lozupone), biostatistics (Dr. Katerina Kechris), and clinical weight loss interventions (Dr. Victoria Catenacci). This training plan combines the exceptional research environment at the University of Colorado Anschutz Medical Campus with generous institutional support and ample resources, as well as an outstanding network of advisors. This work will facilitate the candidate's successful transition to an independent career in molecular epidemiology with the expertise to integ...