PROTEOMIC ANALYSIS OF OXIDATIVE STRESS OF OXIDATIVELY MODIFIED GLYCOLYTIC PROTEI

氧化修饰糖酵解蛋白氧化应激的蛋白质组学分析

• 批准号: 8360121
• 负责人: Tanea Tylette Reed
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360121
• 关键词: Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biological Markers; Biomedical Research; Brain; Chromosomes, Human, Pair 21; Development; Down Syndrome; Energy Metabolism; Energy-Generating Resources; Enzymes; Funding; Glucose; Glyceraldehyde 3-Phosphate; Glycolysis; Grant; Hereditary Disease; Investigation; Location; Metabolic Pathway; Modeling; Modification; National Center for Research Resources; Oxidative Stress; Pathogenesis; Peptides; Persons; Phosphoglycerate Mutase; Principal Investigator; Process; Production; Proteins; Proteomics; Proteus; Psyche structure; Pyruvate; Research; Research Infrastructure; Resources; Source; Staging; Therapeutic; Triose-Phosphate Isomerase; Trisomy; United States National Institutes of Health; base; cost; enolase; enzyme activity; fructose-1,6-diphosphate; glucose metabolism; mild neurocognitive impairment; novel; oxidation; protein function; secretase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In this project, I plan to first examine the amyloid beta hypothesis of Alzheimer's disease (AD) and apply it to a novel Down Syndrome (DS) model by developing a mechanism in which the p3 fragment of the DS preamyloid can possibly be equivalent to the earliest stage of Alzheimer Disease, mild cognitive impairment (MCI). Secondly, by specifically focusing on glycolytic protein oxidation in this model, a basis for the reduced glucose metabolism observed in Alzheimer's disease may be determined and further support of the altered energy metabolism hypothesis of AD may be provided. Investigation of oxidatively modified glycolytic proteins in this novel DS model may also create a new focal point for potential biomarkers in AD and potential therapeutics. Down syndrome is a genetic disease in which persons have reduced mental capacity. Persons with DS have a trisomy at chromosome 21, the location of amyloid precursor protein. This trisomy causes A¿ overproduction, which could possibly be a correlate to the early development of AD in persons with DS. Enzymatic cleavage by ¿-secretase and ¿-secretase forms the toxic p3 fragment, A¿(17-42), which is the major form of A¿ peptide in Down syndrome. No correlation has yet been made between the p3 fragment and AD pathogenesis. Glycolysis is a metabolic pathway that converts glucose to pyruvate and generates 2 ATP molecules in the process. Many key glycolytic enzymes such as ¿-enolase, ¿-enolase, glyceraldehyde 3-phosphate, phosphoglycerate mutase and triosephosphate isomerase are oxidized in AD brain confirming the inability to effectively metabolize glucose, the brain's principal source of energy. In the three progressive stages of Alzheimer's disease, MCI, EAD, and late-stage AD, 70% of glycolytic enzymes undergo oxidative modification, which can greatly affect their enzyme activity and subsequent protein function. All enzymes affected react after the production of fructose 1,6-bisphosphate (FBP). If oxidatively modified pre-FBP proteins are observed in DS, this will provide further support for the altered energy metabolism of AD.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在这个项目中，我计划首先检查阿尔茨海默病（AD）的淀粉样蛋白β假说，并通过开发一种机制将其应用于一种新的唐氏综合征（DS）模型，其中DS淀粉样蛋白的p3片段可能相当于阿尔茨海默病的最早阶段，轻度认知障碍（MCI）。其次，通过特别关注该模型中的糖酵解蛋白氧化，可以确定在阿尔茨海默病中观察到的葡萄糖代谢降低的基础，并且可以提供AD的能量代谢改变假说的进一步支持。在这种新的DS模型中研究氧化修饰的糖酵解蛋白也可能为AD中的潜在生物标志物和潜在治疗方法创造新的焦点。 唐氏综合症是一种遗传性疾病，患者智力下降。患有DS的人在21号染色体上有一个三体，淀粉样前体蛋白的位置。这种三体性导致A？过度产生，这可能与DS患者的AD早期发展相关。通过<$-分泌酶和<$-分泌酶的酶裂解形成毒性p3片段A <$（17-42），其是唐氏综合征中A <$肽的主要形式。尚未发现p3片段与AD发病机制之间的相关性。 糖酵解是将葡萄糖转化为丙酮酸并在此过程中产生2个ATP分子的代谢途径。许多关键的糖酵解酶如<$-烯醇化酶、<$-烯醇化酶、3-磷酸甘油醛、磷酸甘油酸酯酶和磷酸丙糖异构酶在AD脑中被氧化，证实不能有效代谢葡萄糖，葡萄糖是脑的主要能量来源。在阿尔茨海默病的三个进展阶段，MCI，EAD和晚期AD中，70%的糖酵解酶发生氧化修饰，这会极大地影响其酶活性和随后的蛋白质功能。所有受影响的酶在产生果糖1，6-二磷酸（FBP）后反应。如果在DS中观察到氧化修饰的前FBP蛋白，这将为AD的能量代谢改变提供进一步支持。