MR ADIPOSE-O2 QUANTIFICATION AND THE HYPOXIA-DRIVEN INSULIN RESISTANCE HYPOTHESIS

 描述（由申请人提供）：这是华盛顿大学医学院Mallinckrodt放射学研究所博士后研究助理Scott Beeman博士的K01指导研究科学家奖申请。他在开发用于非侵入性测量糖尿病相关生理变化的磁共振技术方面具有很强的背景。在此，他寻求扩大他的科学基础，包括糖尿病病理生理学和临床研究的具体专业知识。主 Beeman博士的目标是成为一名独立的研究者和糖尿病相关成像研究的领导者，因此他提出了一个职业发展计划，他将与世界上代谢和糖尿病专家（Abumrad和Klein博士）以及磁共振和生物物理学专家（阿克曼和Garbow博士）一起培训。从Abumrad和Klein博士那里，他将学到：（i）与2型糖尿病及其发病机制相关的分子和细胞机制，（ii）用于产生2型糖尿病小鼠模型的饲养、基因分型和饮食改良技术，（iii）用于2型糖尿病研究的金标准组织学和测定技术，（iv）临床和转化研究中涉及的伦理和法律的问题，（v）临床研究设计和受试者招募，和（vi）研究人类受试者中的肥胖和2型糖尿病所需的临床技术。从阿克曼和加博博士，他将学习：（一）生物物理学的基础磁共振信号，（二）磁共振脉冲序列设计的深刻理论理解，（三）磁共振硬件开发，以及（四）管理一个主要的研究实验室的细微差别。胰岛素抵抗是2型糖尿病的定义特征，2型糖尿病是一种与肥胖相关的疾病，具有严重的发病率和死亡率。最近的研究表明，脂肪组织缺氧是导致全身胰岛素抵抗级联反应的关键步骤。尽管如此，在胰岛素抵抗发病过程中的纵向脂肪氧分压（pO2）曲线尚未得到解决。在胰岛素抵抗的发病过程中脂肪pO2的特征将是一个重大的进展，了解缺氧驱动的胰岛素抵抗机制。这项工作的目标是：（i）开发方法，以非侵入性地量化体内脂肪氧分压（pO2）与磁共振，（ii）表征脂肪pO2在小鼠的致病性脂肪膨胀的纵向，（iii）证明缺氧驱动的胰岛素抵抗机制在人类，和（iv）表明，运动干预恢复缺氧脂肪常氧在人类。这项提案的更大目标是将比曼博士培养成一名富有成效的独立调查员。在拟议的职业发展和研究计划中获得的知识将为他提供确保R01资金的工具，并作为独立调查员茁壮成长。

 DESCRIPTION (provided by applicant): This is an application for a K01 Mentored Research Scientist Award for Dr. Scott Beeman, a postdoctoral research associate in the Mallinckrodt Institute of Radiology at the Washington University School of Medicine. He has a strong background in developing magnetic resonance techniques for non-invasive measurement of diabetes-related physiologic changes. Herein, he seeks to expand his scientific foundation to include specific expertise in the pathophysiology of diabetes and clinical investigation. A primary goal of Dr. Beeman is to become an independent investigator and a leader in diabetes-related imaging research, thus he proposes a career development plan in which he will train with world's experts in metabolism and diabetes (Drs. Abumrad and Klein) and magnetic resonance and biophysics (Drs. Ackerman and Garbow). From Drs. Abumrad and Klein he will learn: (i) the molecular and cellular mechanisms which relate to type 2 diabetes and its pathogenesis, (ii) husbandry, genotyping, and diet-modification techniques used to produce mouse models of type 2 diabetes, (iii) the gold-standard histological and assay techniques used in type 2 diabetes research, (iv) the ethical and legal issues involved in clinical and translational research, (v) clinical study design and subject recruitment, and (vi) clinical techniques required to study obesity and type 2 diabetes in human subjects. From Drs. Ackerman and Garbow he will learn: (i) a deep theoretical understanding of the biophysics which underpin magnetic resonance signals, (ii) magnetic resonance pulse sequence design, and (iii) magnetic resonance hardware development, and (iv) the nuances of managing a major research laboratory. Insulin resistance is a defining feature of type 2 diabetes - an obesity-related disease with severe morbidity and mortality. Recent studies have suggested that adipose tissue hypoxia is a key step in the cascade that leads to systemic insulin resistance. Still, the longitudinal adipose oxygen partial pressure (pO2) profile during pathogenesis of insulin resistance has not yet been resolved. Characterization of adipose pO2 profile during the pathogenesis of insulin resistance would be a major advance in understanding the hypoxia-driven insulin resistance mechanism. The goals of this work are to: (i) develop methodology to non-invasively quantify in vivo adipose oxygen partial pressure (pO2) with magnetic resonance, (ii) characterize adipose pO2 longitudinally during pathogenic expansion of adipose in mice, (iii) demonstrate the hypoxia-driven insulin resistance mechanism in humans, and (iv) show that exercise intervention restores hypoxic adipose normoxia in humans. The larger goal of this proposal is to develop Dr. Beeman into a productive independent investigator. The knowledge obtained during the proposed career development and research plans will provide him the tools to secure R01 funding and thrive as an independent investigator.