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: 8168301
• 负责人: Tanea Tylette Reed
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168301
• 关键词: Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biological Markers; Brain; Chromosomes, Human, Pair 21; Computer Retrieval of Information on Scientific Projects Database; Development; Down Syndrome; Energy Metabolism; Energy-Generating Resources; Enzymes; Fructose; Funding; Glucose; Glyceraldehyde 3-Phosphate; Glycolysis; Grant; Hereditary Disease; Institution; Investigation; Location; Metabolic Pathway; Modeling; Modification; Oxidative Stress; Pathogenesis; Peptides; Persons; Phosphoglycerate Mutase; Process; Production; Proteins; Proteomics; Proteus; Psyche structure; Pyruvate; Pyruvates; Research; Research Personnel; Resources; Source; Staging; Therapeutic; Triose-Phosphate Isomerase; Trisomy; United States National Institutes of Health; base; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在这个项目中，我计划首先检验阿尔茨海默病(AD)的淀粉样β假说，并将其应用于一种新的唐氏综合征(DS)模型，方法是开发一种机制，在该机制中，DS Preyloid的p3片段可能相当于阿尔茨海默病的早期阶段，即轻度认知障碍(MCI)。其次，通过在该模型中特别关注糖酵解蛋白的氧化，可以确定阿尔茨海默病中观察到的糖代谢降低的基础，并可能进一步支持AD的能量代谢改变假说。在这个新的DS模型中研究氧化修饰的糖酵解蛋白也可能为AD的潜在生物标志物和潜在的治疗创造一个新的焦点。 唐氏综合症是一种遗传性疾病，患有唐氏综合症的人智力下降。患有DS的人在21号染色体上有三体，这是淀粉样前体蛋白的位置。这种三体导致A‘产生过多，这可能与DS患者早期AD的发展有关。分泌酶和分泌酶的酶促裂解形成有毒的p3片段A(17-42)，它是唐氏综合征中A肽的主要形式。P3基因片段与AD发病机制之间的关系尚不清楚。 糖酵解是一种代谢途径，将葡萄糖转化为丙酮酸，并在此过程中产生2个ATP分子。许多关键的糖酵解酶，如β-烯醇化酶、β-烯醇化酶、3-磷酸甘油醛、磷酸甘油酸变位酶和磷酸丙糖异构酶在AD大脑中被氧化，证实了无法有效地代谢大脑的主要能量来源葡萄糖。在阿尔茨海默病的三个进展期，MCI、EAD和晚期AD中，70%的糖酵解酶经历了氧化修饰，这会极大地影响它们的酶活性和随后的蛋白质功能。所有受影响的酶在产生1，6-二磷酸果糖(FBP)后发生反应。如果在DS中观察到氧化修饰的Pre-FBP蛋白，这将为AD能量代谢的改变提供进一步的支持。