Imaging Biomarkers for Evaluating Mitochondrial Function in Diabetes

描述(由申请人提供)：应聘者之前的研究经验主要集中在研究医学成像的基础物理学和技术进步，特别是核磁共振物理学。由于自己的家庭中糖尿病和疾病的患病率越来越高，他开始对应用他的技术技能来研究2型糖尿病(T2 DM)的发病机制感兴趣。这项提议的总体目标是扩大候选人在代谢生物学和临床医学领域的培训和实践经验，为他的研究生涯奠定基础，使用成像方法研究胰岛素抵抗和糖尿病背景下线粒体功能障碍所涉及的过程。本次培训的重点如下。胰岛素是一种重要的葡萄糖代谢调节剂，通过刺激血液中葡萄糖的摄取并促进其作为糖原储存在肝脏和肌肉中，从而影响肝脏、肌肉和脂肪组织。当胰岛素水平正常时，对葡萄糖的摄取异常低，这是一种称为胰岛素抵抗(IR)的情况。骨骼肌胰岛素抵抗增加在瘦肉型和肥胖型糖尿病患者中都很常见。糖尿病患者血糖水平升高导致线粒体产生活性氧物种，这可能会削弱线粒体在胰岛素抵抗中产生足够能量的能力。胰岛素抵抗在骨骼肌代谢中的作用在糖尿病研究中引起了浓厚的兴趣，研究人员正在努力建立一个整体的理论框架来理解这一过程。这种类型的计算机建模将受益于直接从活体受试者的组织中获得的细胞内代谢数据。非侵入性成像技术可以测量一系列生理条件下的新陈代谢过程，从而对模型进行改进。这些数据将补充从切除的组织样本中获得的更具侵入性的分析所获得的信息，包括透射电子显微镜和台式生化分析。磷-31核磁共振波谱可以用来显示胰岛素抵抗受试者的代谢受损。然而，所使用的方法需要进行校准和优化，以便为生理模型提供高度准确的信息。此外，正电子发射断层扫描已被广泛用于测量骨骼肌中葡萄糖的利用和组织血流量。拟议项目的总体目标是开发这些成像方法来测量作为代谢重要中介的骨骼肌中各种化学物质的浓度，测量重要反应的进行速度，测量肌肉血流量和葡萄糖利用率，同时严格控制血糖水平，以便开发和完善导致糖尿病患者骨骼肌胰岛素抵抗的分子和生化机制的计算机模型。人们希望这些工具将导致对糖尿病发病的更好理解，并允许开发能够缓解与糖尿病相关的胰岛素抵抗状况的治疗方法。 公共卫生相关性：这项研究使用磁共振光谱成像(MRS)和正电子发射断层扫描(PET)，非侵入性地检查产生人类数据所需的因素。所获得的信息将用于评估胰岛素抵抗综合征和糖尿病患者的线粒体功能。该项目包括一个旨在将当代生物化学知识提高到研究生水平的培训制度。此外，实验室和临床研究培训将使用胰岛素抵抗的临床测量方法、氧-15-水和氟-18-脱氧葡萄糖的正电子发射计算机断层扫描(PET)成像、分离线粒体新陈代谢分析。该项目包括开发、验证和使用磷-31MRS成像和PET成像的计划，以微创方式评估患者和胰岛素抵抗受试者线粒体的代谢状态。

DESCRIPTION (provided by applicant): The candidate's previous research experience has focused on studying the basic physics and technological advances of medical imaging, particularly MRI physics. Due to the increasing prevalence of diabetes and afflictions in the own candidate's family, he has become interested in applying his technical skills to investigate the pathogenesis of type 2 diabetes mellitus (T2DM). The overall goal of this proposal is to expand the candidate's training and practical experience in areas of metabolic biology and clinical medicine to position him for a research career using imaging methods to study the processes involved in mitochondrial dysfunction in the setting of insulin resistance and diabetes. The focus of this training is described below. Insulin is an important regulator of glucose metabolism that affects liver, muscle and fat tissue by stimulating glucose uptake from blood and promoting its storage as glycogen in liver and muscle. Abnormally low uptake of glucose, when there are normal insulin levels, is a condition known as insulin resistance (IR). Increased insulin resistance in skeletal muscle is common in both lean and obese diabetic subjects. The increased glucose levels in diabetes lead to production of reactive oxygen species in mitochondria, which probably impairs the ability of mitochondria to produce adequate energy in insulin resistance. The action of insulin resistance in skeletal muscle metabolism is of intense interest in diabetes research and investigators are working on an overall theoretical framework to understand the processes. This type of computer modeling would benefit from intracellular metabolic data acquired directly from the tissues of livings subjects. Noninvasive imaging technologies can measure metabolic processes under a range of physiological conditions, allowing refinement of the models. These data would supplement information obtained from more invasive analyses from excised tissue samples, including transmission electron microscopy and bench top biochemical assays. Phosphorus-31 nuclear magnetic resonance spectroscopy can be used to demonstrate impaired metabolism in subjects with insulin resistance. However the methods used need to be calibrated and optimized to supply highly accurate information for physiological models. Also, positron emission tomography has been used extensively to measure glucose utilization and tissue blood flow in skeletal muscle. The overall goals of the proposed project are to develop these imaging methods to measure the concentrations of various chemicals in skeletal muscle that are important intermediaries of metabolism, measure the rate at which important reactions progress, measure muscle blood flow and measure glucose utilization rate, while the blood glucose level is being strictly controlled in order to develop and refine computer models of molecular and biochemical mechanisms that contribute to insulin resistance in the skeletal muscle of diabetic patients. It is hoped that these tools will lead to improved understanding of the onset of diabetes and allow development of therapies that can alleviate the insulin resistant condition associated with diabetes. PUBLIC HEALTH RELEVANCE: This research examines factors necessary for producing data on humans, noninvasively using magnetic resonance spectroscopic imaging (MRS) and positron emission tomography (PET). The information obtained will be used to evaluate mitochondrial function in patients with insulin resistance syndrome and diabetes. The project consists of a training regime that that is designed to increase the knowledge of contemporary biochemistry to a graduate level. This will be complemented by laboratory and clinical research training in the use of clinical measures of insulin resistance, PET imaging with oxygen-15-water and fluorine-18- deoxyglucose, assays of the metabolism of isolated mitochondria. The project includes a plan to develop, validate and employ both phosphorus-31 MRS imaging and PET imaging to evaluate the metabolic status of the mitochondria in patients and insulin resistant subjects in a minimally invasive manner.