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

多组学方法了解运动对糖尿病的有益影响

• 批准号: 10448692
• 负责人: Maria Vamvini
• 金额: $ 6.53万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448692
• 关键词: Adipose tissue; Aging; Animals; Area; Bioinformatics; Biological; Biological Process; Blood; Blood Circulation; Brain; Cells; Chronic; Chronic Disease; Collection; Communication; Computational Biology; Data; Data Analyses; Development; Diabetes Mellitus; Diet; Disease; Emerging Technologies; Event; Exercise; Exercise Physiology; Fatty acid glycerol esters; Gene Expression Profile; Genes; Genetic Transcription; Glucose Intolerance; Goals; Health; Health Benefit; Heterogeneity; High Fat Diet; Hippocampus (Brain); Housing; Human; Hypothalamic structure; Individual; Insulin Resistance; Intestines; Lead; Maps; Measurement; Mediating; Memory; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular; Mus; Muscle; Neurodegenerative Disorders; Obese Mice; Obesity; Pathway interactions; Phase; Physical activity; Physicians; Physiological; Play; Process; Proteins; Rattus; Research; Rodent; Role; Running; Sampling; Scientist; Skeletal Muscle; Small Intestines; Stimulus; Structure of thyroid parafollicular cell; Technology; Thinness; Tissues; Training; Transducers; Triceps Brachii Muscle; United States National Institutes of Health; Visceral; Work; body system; cardiovascular health; cell type; cognitive function; complex data; data integration; diet and exercise; diet-induced obesity; exercise training; experimental study; improved; metabolomics; multiple omics; new therapeutic target; novel therapeutics; obesity treatment; prevent; response; sedentary; single cell analysis; stem; subcutaneous; therapeutic target; tool; training opportunity; transcriptome; transcriptomics

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.

项目摘要 确定介导运动对健康有益的分子机制是一个具有挑战性的， 这是一项重要的任务，可以导致新的治疗靶点的鉴定。其意义 美国国立卫生研究院发起的大规模“身体活动的分子传感器”项目强调了这一研究领域 联盟”（MoTrPAC），旨在了解健康人运动的分子足迹， 大鼠虽然MoTrPAC提供的广泛，深入的数据将是一个具有里程碑意义的项目，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 和其他代谢疾病可能仍然在很大程度上未知，即使在后MoTrPAC时代。的总目标 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， 改善代谢疾病条件下的健康状况。具体目的是确定：a）组织特异性 响应于运动和饮食的细胞类型和细胞组成的变化; B）组织特异性转录 反应和激活的分子途径，可以扭转不利的代谢影响的饮食- 诱导的肥胖;和c）瘦小鼠和肥胖小鼠中的细胞类型和组织串扰。分析这些复杂的 使用计算生物学工具的数据有能力解开疾病的分子基础， 治疗目标这个大型项目分两个阶段。第一阶段包括收集多个 来自用或不用运动治疗的胰岛素抵抗小鼠的组织，第二阶段是多组学的， 生物信息学分析这些样本。该项目的第一阶段最近已由 申请人，允许一个可行的2年研究计划，以完成该项目的第二阶段。第一 阶段，将小鼠分为四组：久坐不动的饲料喂养;训练的饲料喂养;久坐不动的高脂肪饮食喂养;和 高脂肪食物喂养的。饮食处理持续6周，并且通过将小鼠圈养在动物园中进行运动训练。 3周内免费使用转轮。已知在代谢中起重要作用的七种组织是 采集：三头肌、皮下和内脏白色脂肪组织、小肠、下丘脑、海马 和大脑皮层。该项目的第二阶段是对所有人进行单细胞转录组学和代谢组学研究。 收集的组织，然后使用计算生物学工具进行数据分析和整合。申请人的 培训计划将包括由劳里博士固特异（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（共同赞助商）的多组学方法和计算 生物学申请人还将通过哈佛和麻省理工学院完成正式的生物信息学培训。这些活动 将为她提供必要的工具，作为一个独立的医生科学家的发展至关重要。这 项目不仅为申请人提供了一个出色的培训机会，而且还应导致 这些发现对肥胖和糖尿病的治疗具有广泛意义。

项目成果

Novel interactive text-messaging curriculum for endocrinology board review.

• DOI: 10.1016/j.jcte.2023.100326
• 发表时间: 2023-12
• 期刊: JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY
• 影响因子: 3
• 作者: Majety, Priyanka;Ajayi, Ayodele;Modest, Anna M.;Vamvini, Maria;Freed, Jason A.
• 通讯作者: Freed, Jason A.

Characteristics and Diabetes Control in Adults With Type 1 Diabetes Admitted With COVID-19 Infection.

• DOI: 10.2337/dc20-1540
• 发表时间: 2020-10
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Vamvini M;Lioutas VA;Middelbeek RJW
• 通讯作者: Middelbeek RJW