Multi-omics approach to understanding the beneficial effects of exercise in diabetes

项目总结 确定运动对健康有益的分子机制是一项具有挑战性的工作，但也是极其困难的。 这是一项重要的工作，可导致确定新的治疗靶点。这件事的意义 美国国立卫生研究院的大规模倡议“体力活动分子传感器”强调了这一研究领域 联合会“(MoTrPAC)，其目的是了解运动在健康人类和 老鼠。虽然MoTrPAC提供的广泛、深入的数据将是一个里程碑式的项目，但该联盟将 只研究健康的人类和啮齿动物。因此，肥胖条件下运动的分子足迹 即使在后MoTrPAC时代，其他代谢性疾病可能在很大程度上仍是未知的。的总目标是 这个项目是使用最先进的组学平台来发现运动训练的机制 改善代谢性疾病条件下的健康状况。具体目标是确定：a)组织特异性 运动和饮食引起的细胞类型和细胞组成的变化；b)组织特异性转录 可以逆转饮食不利代谢影响的分子途径的反应和激活- 诱导肥胖；以及c)瘦小鼠和肥胖小鼠的细胞类型和组织串扰。对这些情结的分析 使用计算生物学工具的数据有能力解开疾病的分子基础并识别 治疗靶点。这一大型项目分为两个阶段。第一阶段包括收集多个 胰岛素抵抗小鼠的组织经过或不经过运动治疗，第二阶段是多组学和 对这些样本进行生物信息学分析。该项目的第一阶段最近已由 申请人，允许一个可行的两年研究计划，以完成项目的第二阶段。对于第一次 在阶段，小鼠被分成四组：久坐饮食；训练饮食；久坐高脂饮食； 训练有素的高脂肪饮食。饮食治疗为期6周，运动训练通过饲养小鼠进行。 免费使用跑轮3周。已知在新陈代谢中起重要作用的七种组织是 收集：三头肌、皮下和内脏白色脂肪组织、小肠、下丘脑、海马体 和大脑皮层。该项目的第二阶段是对ALL进行单细胞转录和代谢组学研究 收集组织，然后使用计算生物学工具进行数据分析和整合。申请人的 培训计划将包括劳里·古德伊尔博士(赞助商)在运动领域的专门指导， 代谢和糖尿病，以及Manolis Kellis博士(多组学方法和计算方法的共同发起人) 生物学。申请者还将通过哈佛大学和麻省理工学院完成正式的生物信息学培训。这些活动 将为她提供作为一名独立内科科学家发展至关重要的必要工具。这 该项目不仅将为申请者提供出色的培训机会，而且还应导致 这些发现对肥胖和糖尿病的治疗具有广泛的意义。

PROJECT SUMMARY Determining the molecular mechanisms mediating the health benefits of exercise is a challenging, but extremely important undertaking, that can lead to the identification of novel therapeutic targets. The significance of this area of research is underscored by the large-scale NIH initiative “Molecular Transducers of Physical Activity Consortium” (MoTrPAC), which aims to understand the molecular footprint of exercise in healthy humans and rats. While the extensive, in-depth data provided by MoTrPAC will be a landmark project, this consortium will only study healthy humans and rodents. Thus, the molecular footprint of exercise under conditions of obesity and other metabolic diseases may remain largely unknown, even in the post-MoTrPAC era. The overall goal of this project is to use state-of-the art omics platforms to discover the mechanism by which exercise training improves health under conditions of metabolic disease. Specific Aims are to determine: a) tissue-specific changes in cell types and cell composition in response to exercise and diet; b) tissue-specific transcriptional responses and activation of molecular pathways that can reverse the unfavorable metabolic effects of diet- induced obesity; and c) cell-type and tissue crosstalk in both lean and obese mice. Analysis of these complex data using computational biology tools has the power to unravel the molecular basis of disease and identify therapeutic targets. This large-scale project has two phases. The first phase includes the collection of multiple tissues from insulin resistant mice treated with or without exercise and second phase is multi-omics and bioinformatics analysis of these samples. The first phase of this project has recently been completed by the applicant, allowing for a feasible 2-year research plan to complete the second phase of the project. For the first phase, mice were divided in four groups: sedentary chow-fed; trained chow-fed; sedentary high fat diet-fed; and trained high fat diet-fed. Diet treatments were for 6 weeks and exercise training was done by housing mice with free access to a running wheel for 3 weeks. Seven tissues known to play significant roles in metabolism were collected: triceps, subcutaneous and visceral white adipose tissue, small intestine, hypothalamus, hippocampus and brain cortex. Phase 2 of this project is to perform single-cell transcriptomics and metabolomics on all collected tissues followed by data analysis and integration using computational biology tools. The applicant’s training plan will include dedicated mentorship by both Dr. Laurie Goodyear (sponsor) in the areas of exercise, metabolism, and diabetes, and Dr. Manolis Kellis (co-sponsor) for multi-omic approaches and computational biology. The applicant will also complete formal bioinformatics training through Harvard and MIT. These activities will provide her with the necessary tools critical for development as an independent physician scientist. This project will not only provide an outstanding training opportunity for the applicant, but should also lead to discoveries with broad implications for the treatment of obesity and diabetes.