Hyperpolarized 13C Markers of Diabetic Nephropathy and Treatment Response

糖尿病肾病的超极化 13C 标志物和治疗反应

• 批准号: 8578772
• 负责人: Zhen Jane Wang
• 金额: $ 23.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578772
• 关键词: Accounting; Advanced Glycosylation End Products; Albumins; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Attention; Biological Markers; Bioreactors; Cell Culture Techniques; Clinical; Clinical Markers; Creatinine clearance measurement; DNA; Dehydroascorbic Acid; Deoxyguanosine; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diagnosis; Dihydroxyacetone Phosphate; Disease; Disease Progression; Early Diagnosis; End stage renal failure; Evaluation; Fructose; Glucose; Glutathione; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Goals; Hexoses; Histology; Human; Hyperglycemia; Imaging Techniques; Imaging technology; Injury; Kidney; Kidney Diseases; Label; Lead; Link; Magnetic Resonance; Magnetic Resonance Imaging; Metabolic; Metabolism; Methods; Modeling; Molecular; Monitor; Motivation; Mus; NADP; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Physiological Processes; Preparation; Prevention; Pyruvaldehyde; Ramipril; Reactive Oxygen Species; Serum Markers; Signal Transduction; Source; Sulforaphane; Superoxides; Testing; Thiamine; Tissues; Toxic effect; Transketolase; Translations; United States; Urine; Work; advanced disease; cell type; db/db mouse; dehydroascorbate; diabetic; glucose metabolism; hexokinase; imaging modality; improved; in vivo; magnetic resonance spectroscopic imaging; mesangial cell; molecular imaging; mortality; mouse model; novel; nuclear factor-erythroid 2; public health relevance; rapid detection; response; response to injury; sensor; treatment response

DESCRIPTION (provided by applicant): Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. Non-invasive biomarkers to evaluate the initiation and progression of disease are currently limited. The goal of this project is to develop hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopic imaging methods that interrogate key metabolic changes underlie diabetic nephropathy, namely altered oxidative stress and glycolytic metabolism, which may improve the early diagnosis and monitoring of targeted treatment of diabetic renal injury. HP 13C MR is a new molecular imaging technique that provides an unprecedented gain in sensitivity (>10,000-fold increase) for detecting 13C-labeled bio-molecules, and allows rapid detection of alterations in metabolic and physiologic processes noninvasively. Recently, we have developed two novel HP probes: (1) the redox sensor HP 13C-dehydroascorbate (DHA), an oxidized version of Vitamin C, and (2) HP 13C-fructose, a hexose probe that evaluates the early steps of glycolysis. We will apply these new probes to a 3D perfused cell culture or "bioreactor" platform, and a well-characterized murine model of diabetes in order to carry out the Specific Aims of this proposal. In Aim 1, we will determine the key molecular mechanism underlying in vivo HP 13C-DHA reduction to Vitamin C, and examine renal redox states using HP 13C-DHA during the progression of renal injury from diabetes. In Aim 2, we will investigate the renal glycolytic metabolism in diabetes using HP 13C-fructose, and relate the observed metabolic flux to the enzymatic activity of glyceraldehydes-3 phosphate dehydrogenase (GAPDH). Inactivation of GAPDH with accumulation of glycolytic intermediates is critically linked to the many damaging pathways in diabetic nephropathy. In Aim 3, we will monitor treatment response to an angiotensin converting enzyme inhibitor (Ramipril), a nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activator (Sulforaphane), and a transketolase activator (Thiamine) using the HP probes, with particular attention to the agents' targeted effects on oxidative stress and glycolytic metabolism. The HP probes in this study are comprised of endogenous bio-molecules that are anticipated to have minimal toxicities in humans, and therefore have high potential for clinical translation. Successful completion of the aims will lead to noninvasive biomarkers that may enhance monitoring the onset and progression of diabetic nephropathy, and response to therapy.

描述（由申请人提供）：糖尿病性肾病是美国终末期肾脏疾病的主要原因。目前，评估疾病开始和进展的非侵入性生物标志物受到限制。该项目的目的是发展超极化 （HP）13C磁共振（MR）光谱成像方法询问关键代谢变化是糖尿病肾病的基础，即改变了氧化应激和糖酵解代谢，这可以改善对糖尿病损伤的靶向治疗的早期诊断和监测。 HP 13C MR是一种新的分子成像技术，可用于检测13C标记的生物分子的灵敏度（> 10,000倍）的前所未有的增益，并允许快速检测代谢和生理过程的改变。最近，我们开发了两个新型的HP探针：（1）氧化还原传感器HP 13C-脱氧剂（DHA）（DHA），一种氧化的维生素C，（2）HP 13C-Fructose，是一种评估糖酵解早期步骤的己糖探针。我们将将这些新探针应用于3D灌注细胞培养物或“生物反应器”平台，以及糖尿病的特征性鼠模型，以执行该建议的具体目的。在AIM 1中，我们将确定体内HP 13C-DHA减少维生素C的关键分子机制，并在糖尿病肾脏损伤过程中使用HP 13C-DHA检查肾脏氧化还原态。在AIM 2中，我们将使用HP 13C-果糖研究糖尿病中的肾糖酵解代谢，并将观察到的代谢通量与甘油醛-3磷酸脱氢酶（GAPDH）的酶活性相关联。与糖酵解中间体积累的GAPDH失活与糖尿病性肾病中许多有害途径密切相关。在AIM 3中，我们将监测对血管紧张素转化酶抑制剂（Ramipril）的治疗反应，这是一种核因子2相关因子2（NRF2）途径激活剂（Sulforforaphane）和使用HP探针，使用HP探针，使用Transketolase激活剂（Thiamine）特别注意代理商的目标效应 关于氧化应激和糖酵解代谢。这项研究中的HP探针由内源性生物分子组成，预计该分子在人类中的毒性最少，因此具有很高的临床翻译潜力。成功完成目标将领导 对于可以增强糖尿病性肾病的发作和进展以及对治疗的反应的无创生物标志物。