Investigating the polyol pathway in the human brain

研究人脑中的多元醇途径

• 批准号: 9089213
• 负责人: Janice Jin Hwang
• 金额: $ 17.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089213
• 关键词: Acute; Adverse effects; Affect; Aldehyde Reductase; Appetite Stimulants; Attention; Blood Glucose; Brain; Bypass; Cardiovascular Diseases; Cardiovascular system; Cerebrospinal Fluid; Chronic; Complications of Diabetes Mellitus; Diabetes Mellitus; Diabetic Retinopathy; Disease; Environment; Euglycemic Clamping; Exposure to; Fasting; Fatty Liver; Feeding behaviors; Foundations; Fructose; Functional disorder; Future; Generations; Glucose; Glucose Clamp; Glutathione; Glycolysis; Goals; Hour; Human; Human body; Hyperglycemia; Image; Impaired cognition; Individual; Infusion procedures; Insulin; Intravenous; Kidney Diseases; L-Iditol 2-Dehydrogenase; Lead; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolism; Methodology; NMR Spectroscopy; Neuraxis; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Physiological; Physiology; Plasma; Play; Prevalence; Process; Production; Protocols documentation; Research; Research Personnel; Retinal Diseases; Role; Severities; Sorbitol; Techniques; Technology; Testing; Time; Training; Treatment Protocols; Work; base; career; combat; diabetes management; diabetic; experience; glycemic control; healthy weight; imaging modality; improved; inhibitor/antagonist; insight; medical schools; metabolic abnormality assessment; multidisciplinary; neurovascular; non-diabetic; novel; novel strategies; polyol; public health relevance; response; skills

 DESCRIPTION (provided by applicant): The rising prevalence of type 2 diabetes mellitus (T2DM) amongst both younger and older individuals has led to increases in the lifetime exposure to T2DM. A growing body of evidence suggests that chronic hyperglycemia and T2DM leads to many adverse effects on brain function, particularly neurovascular disorders and cognitive impairment. However, the underlying mechanisms behind these associations remain unclear. The purpose of this application is to evaluate the role of the polyol pathway as a potential mediator of the CNS effects of hyperglycemia. The polyol pathway (glucose  sorbitol  fructose) is an alternate glucose pathway that is present throughout the human body, including the brain. In addition to fructose generation, polyol pathway activity has also been associated with increased oxidative stress and has been linked to the complications of diabetes including diabetic retinopathy, neuropathy and cardiovascular disease. However, the role of this pathway in the brain remains unclear. This K23 application will investigate the potential role of the polyol pathway in mediating the central nervous system effects of hyperglycemia by using nuclear magnetic resonance spectroscopy (MRS) which allows for the non-invasive measurements of brain metabolites as well as metabolic study methodology to alter peripheral glucose levels. The results from the physiology-based human studies in both healthy individuals as well as individuals with poorly controlled T2DM in this application will provide insights regarding whether the polyol pathway contributes to the endogenous production of fructose from glucose in the human brain as well as whether excessive activity through the pathway is associated with measures of increased oxidative stress in the brain. This research application will capitalize on the rich academic environment at Yale School of Medicine where a team of multidisciplinary independent investigators have joined together to utilize cutting edge imaging methodologies to investigate central questions in metabolism. Dr. Hwang, the Candidate for this K23 application, will gain important experience in the conduct and analysis of studies using MRS as well as metabolic techniques such as glucose clamp methodology. The findings from this study will lay the foundation for future studies targeting the polyol pathway to combat the central nervous system effects of diabetes and will help Dr. Hwang establish a long-term career as an independent investigator with an expertise in using state-of-the-art imaging modalities to understand the central nervous system effects of diabetes.

 描述（由适用提供）：在年轻人和年龄较大的个体中，2型糖尿病（T2DM）的患病率上升导致终生暴露于T2DM。越来越多的证据表明，慢性高血糖和T2DM会导致对脑功能的不利影响，尤其是神经血管疾病和认知障碍。但是，这些关联背后的基本机制尚不清楚。本应用的目的是评估多元途径作为高血糖效应的潜在介体的作用。多元醇途径（葡萄糖山梨糖醇果糖）是一种替代性葡萄糖途径，它存在于整个人体，包括大脑。除果糖产生外，多元途径活性还与氧化应激增加有关，并且与包括糖尿病性视网膜病，神经病和心血管疾病在内的糖尿病并发症有关。但是，该途径在大脑中的作用尚不清楚。该K23应用将通过使用核磁共振光谱法（MRS）来研究多元途径在介导高血糖的中枢神经系统影响中的潜在作用，该光谱谱法（MRS）允许对脑代谢产物的非侵入性测量以及代谢研究方法来改变周围葡萄糖水平。在本应用中，基于生理学的人类研究以及控制T2DM不良的个体的人类研究的结果将提供有关多元型途径是否有助于人脑中葡萄糖的果糖的内源性产生的见解，以及通过该途径过度活性与大脑中氧化应激增加的测量有关。 该研究申请将利用耶鲁大学医学学院丰富的学术环境，其中一组跨学科独立研究人员联合在一起利用尖端成像方法来研究代谢中的中心问题。 Hwang博士是该K23应用的候选人，将在使用MRS以及葡萄糖夹方法等代谢技术的研究中获得重要经验和分析。这项研究的发现将奠定针对以对抗糖尿病的中枢神经系统影响的未来研究的基础，并将帮助Hwang博士建立长期的职业生涯，是独立研究者，专家使用最先进的成像方式来了解糖尿病的中枢神经系统的影响。