Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging

 描述（由申请人提供）：我的职业目标是成为一名独立的NIH R 01资助的研究人员，有助于更好地了解支持异质性糖尿病和肥胖相关代谢风险的病理生理学。迄今为止，我的工作主要集中在脂肪组织结构分布的静态评估，最终在许多第一作者的出版物和研究奖项。推进该领域和我自己的职业发展所需的两个直接研究目标是：1）获得纵向评估内脏脂肪组织（VAT）分布变化的新技能; 2）使用新的成像技术将我的研究计划从脂肪组织分布研究扩展到脂肪组织功能研究，以便更好地了解过量VAT导致代谢疾病的机制。为了实现这些目标，我已经形成了一个专门的和严格的职业发展计划，将包括多学科的指导，流行病学，生物统计学和生物医学成像课程，最终完成硕士学位临床科学，并在脂肪组织成像和翻译方法的分析和解释的直接培训。我将继续我与James de Lemos博士成功的指导关系，并与代谢成像专家兼UTSW高级成像研究中心（AIRC）主任克雷格马洛伊博士开展指导合作。此外，我将继续与格洛丽亚维加博士和斯科特格伦迪博士的合作关系，我将与他们一起训练成像技术和体脂分布分析。在这项资助的背景下，我将与达拉斯心脏研究（DHS）的主要研究者、代谢疾病专家海伦·霍布斯博士以及著名的糖尿病和脂质代谢研究人员豪尔赫·普卢茨基博士建立正式关系。我的长期目标是了解增值税如何导致糖尿病风险，并确定减少增值税过度代谢后果的策略。本提案的目的是描述VAT变化与糖尿病风险之间的关系，并阐明VAT与血糖稳态异常之间的机制关系。在这里，我将测试中心假设，内脏肥胖在DHS中胰岛素抵抗和糖尿病的发病机制中起着关键作用，DHS是一项多种族队列研究，其中VAT已连续测量双X线吸收测定法和糖尿病结局已收集超过10年的随访。这些流行病学研究将通过使用经过充分验证的核磁共振（NMR）光谱平台进行的肝硬化发生中甘油代谢的功能研究进行补充。我将通过以下三个具体目标实现本提案的科学目标：1）表征达拉斯心脏研究中10年期间VAT变化与糖尿病风险之间的相关性，2）通过NMR光谱测量血糖中甘油的富集，阐明VAT质量与葡萄糖稳态之间的关系，3）确定恩格列净的作用，一种新的糖尿病药物，显示出减少VAT标志物，对具有不同VAT质量的非糖尿病肥胖成人的葡萄糖稳态的影响。这些研究预计将产生重要的积极影响，因为所确定的关系极有可能改善糖尿病风险的评估，为糖尿病的预防和治疗干预提供新的目标，并从根本上推进肥胖研究领域。UT西南结合了非凡的流行病学和转化研究机会和教师发展计划，这将确保PI的成功的临床研究生涯。这些机构包括国土安全部（由德莱莫斯博士和霍布斯博士领导）、AIRC（由马洛伊博士领导）、人类营养中心（由格伦迪博士和维加博士领导）、肥胖研究工作组、临床科学系、转化医学中心和糖尿病研究试金石中心。基于我的培训、经验、合作关系和机构环境，我相信我有独特的能力实现以下目标： 这个职业发展项目，并成熟为一个独立的研究者能够应用新的成像和翻译技术，直接询问的结构和功能的增值税，以回答重要的流行病学和临床问题的作用，过量增值税作为减少糖尿病和代谢疾病的目标。

 DESCRIPTION (provided by applicant): My career goal is to become an independent NIH R01-funded investigator contributing to a better understanding of the pathophysiology underpinning the heterogeneous diabetes and metabolic risks associated with obesity. My work to date has been primarily focused on static assessments of adipose tissue structural distribution, culminating in many first-author publications and research awards. The two immediate research goals necessary to advance the field and my own career development are to 1) acquire new skills in the longitudinal assessment of changes in visceral adipose tissue (VAT) distribution and 2) extend my research program from study of adipose tissue distribution to that of adipose tissue function using novel imaging techniques, in order to better understand mechanisms by which excess VAT contributes to metabolic disease. To achieve these goals, I have formed a dedicated and rigorous career development plan that will include multi-disciplinary mentorship, coursework in epidemiology, biostatistics, and biomedical imaging, culminating in completion of a Master's degree in Clinical Sciences, and direct training in the analysis and interpretation of adipose tissue imaging and translational methods. I will continue my successful mentored relationship with Dr. James de Lemos and have initiated a mentored collaboration with Dr. Craig Malloy, an expert in metabolic imaging and Director for the Advanced Imaging Research Center (AIRC) at UTSW. Additionally, I will continue collaborative relationships with Dr. Gloria Vega and Dr. Scott Grundy with whom I will work to train in imaging techniques and analysis of body fat distribution. In the context of this grant, I will formalize ne relationships with Dr. Helen Hobbs, the primary investigator for the Dallas Heart Study (DHS) and an expert in metabolic disease, as well as Dr. Jorge Plutzky, a renowned researcher in diabetes and lipid metabolism. My long term goal is to understand how VAT contributes to diabetes risk and to identify strategies to reduce the metabolic consequences of excess VAT. The objectives of this proposal are to characterize the relationship between changes in VAT and diabetes risk and elucidate the mechanistic relationship between VAT and abnormal glucose homeostasis. Here, I will test the central hypothesis that visceral adiposity plays a key role in te pathogenesis of insulin resistance and diabetes in the DHS, a multiethnic cohort study in which VAT has been serially measured with dual x-ray absorptiometry and diabetes outcomes have been collected over 10 years of follow-up. These epidemiologic studies will be complemented by functional studies of glycerol metabolism in hepatic gluconeogenesis using a well-validated nuclear magnetic resonance (NMR) spectroscopy platform. I will achieve the scientific objectives of this proposal by pursuing the following three specific aims: 1) Characterize the associations between changes in VAT and diabetes risk over a 10 year period in in the Dallas Heart Study, 2) Elucidate the relationship between VAT mass and glucose homeostasis by measuring enrichment of glycerol in blood glucose by NMR spectroscopy, and 3) Determine the effect of empagliflozin, a novel diabetes drug shown to reduce markers of VAT, on glucose homeostasis in non-diabetic obese adults with differing VAT mass. These studies are expected to have an important positive impact, because the identified relationships are highly likely to improve assessment of diabetes risk, lead to new targets for preventive and therapeutic interventions for diabetes, and fundamentally advance the field of adiposity research. UT Southwestern combines extraordinary epidemiologic and translational research opportunities and faculty development programs that will ensure the PI's successful clinical research career. These include the DHS (led by Drs. de Lemos and Hobbs), the AIRC (led by Dr. Malloy), the Center for Human Nutrition (led by Drs. Grundy and Vega), the Taskforce for Obesity Research, the Department of Clinical Sciences, the Center for Translational Medicine, and the Touchstone Center for Diabetes Research. Based on my training, experience, collaborative relationships, and institutional environment, I believe that I am uniquely positioned to achieve the objectives of this career development project and mature into an independent investigator able to apply novel imaging and translational techniques that directly interrogate the structure and function of VAT to answer important epidemiological and clinical questions regarding the role of excess VAT as a target for reducing diabetes and metabolic disease.