Investigating the polyol pathway in the human brain

研究人脑中的多元醇途径

• 批准号: 9322333
• 负责人: Janice Jin Hwang
• 金额: $ 19.31万
• 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/9322333
• 关键词: Acute; Adverse effects; Affect; Aldehyde Reductase; Appetite Stimulants; Attention; Blood Glucose; Brain; Bypass; Cardiovascular Diseases; Cardiovascular system; Cerebrospinal Fluid; Chronic; Closure by clamp; 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; Glycosylated hemoglobin A; 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; Methodological Studies; 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; virtual

 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（由申请人提供）：年轻人和老年人中 2 型糖尿病 (T2DM) 的患病率不断上升，导致终生接触 T2DM 的人数增加。越来越多的证据表明，慢性高血糖和 T2DM 会导致许多不良后果。然而，这些关联背后的潜在机制仍不清楚，该应用的目的是评估多元醇途径作为中枢神经系统潜在介质的作用。多元醇途径（葡萄糖 → 山梨醇 → 果糖）是一种替代葡萄糖途径，存在于整个人体（包括大脑）中。除了果糖的产生外，多元醇途径的活性也与氧化应激的增加有关。与糖尿病并发症有关，包括糖尿病视网膜病变、神经病变和心血管疾病。然而，该通路在大脑中的作用仍不清楚。通过使用核磁共振波谱（MRS），多元醇途径在介导高血糖的中枢神经系统影响中的潜在作用，允许对大脑代谢物进行非侵入性测量以及代谢研究方法来改变外周血糖水平。本应用中对健康个体以及 T2DM 控制不佳的个体进行的基于生理学的人类研究将提供关于多元醇途径是否有助于从人脑中的葡萄糖内源性生产果糖以及过度活动是否有助于深入了解通过该途径与大脑中氧化应激增加的测量有关。 该研究应用将利用耶鲁大学医学院丰富的学术环境，该学院由多学科独立研究人员组成的团队联合起来，利用尖端的成像方法来研究代谢中的核心问题。该 K23 应用的候选人黄博士将。在使用 MRS 以及葡萄糖钳夹方法等代谢技术进行和分析研究方面获得重要经验，这项研究的结果将为未来针对多元醇途径对抗糖尿病中枢神经系统影响的研究奠定基础。帮助黄医生建立作为独立研究者的长期职业生涯，拥有使用最先进的成像方式了解糖尿病对中枢神经系统影响的专业知识。