The Contribution of Omic Profiles to Weight Loss and Obesity

项目摘要 心血管疾病（CVD）的发展是一个复杂的过程，肥胖是一个主要的危险因素。 超重/肥胖个体的体重减轻是CVD一级预防的关键组成部分，但 个体对生活方式减肥干预的反应存在显著差异。至关重要 提高我们对减肥反应驱动因素的理解，因为这可能有助于确定 肥胖，并可能最终导致新的或更个性化的预防或治疗机会。本研究 将研究遗传学，肠道微生物群（GM）和代谢物如何有助于测量 在标准减肥方法的持续1年生活方式减肥试验期间，每天 热量限制（DCR）与一种新的替代方法，间歇性禁食（IMF）。这种对因果关系的理解 干预环境中组学特征与体重减轻/健康改善之间的关系将针对 一项关于转基因和代谢物作为遗传性肥胖风险与肥胖症之间联系的中介的研究， 肥胖相关的表型在更大的流行病学队列。来自参与者子集的初步数据， 提供可行性证据并为以下创新目标的假设提供信息的干预措施： 目标1：评估GM和代谢物的纵向变化，以及这些变化的主要驱动因素 在DCR与IMF的生活方式减肥干预期间发生变化。目标2：评估 在生活方式减肥期间，肥胖和GM/代谢产物的遗传风险测量与反应性 干预目的3：研究GM/代谢物是否介导多种族之间的关联 两个流行病学队列中肥胖多基因风险评分和肥胖测量。 该职业发展奖还将为候选人提供获得重要技能的机会 和专业知识。她有一个明确的计划，以获得培训有关：1）处理猎枪宏基因组转基因， 代谢组学数据; 2）因果推理和其他用于分析多组学数据的相关方法;和3） 多种族多基因风险评分。培训计划包括课程作业、会议出席和亲自参加 与知名学者的培训，以及知名领导者导师团队的指导， 他们各自的遗传流行病学领域（Leslie Lange博士;主要导师），生物信息学和 人类肠道微生物组（Catherine Lozupone博士）、生物统计学（Katerina Kechris博士）和临床减肥 （维多利亚Catenacci博士）。这项培训计划结合了在特殊的研究环境， 科罗拉多大学安舒茨医学院拥有慷慨的机构支持和充足的资源， 以及一个优秀的顾问网络。这项工作将有助于候选人成功过渡到 分子流行病学的独立职业，具有将复杂类型的组学数据整合到 为了提高我们对疾病病理生理学的理解，并为创新的预防和 肥胖和心血管疾病的干预措施。

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 integrate complex types of omics data in order to improve our understanding of disease pathophysiology and to inform innovative prevention and intervention efforts for obesity and CVD.