Proteomic Studies of Age Related Macular Degeneration

年龄相关性黄斑变性的蛋白质组学研究

• 批准号: 6942253
• 负责人: JOHN W CRABB
• 金额: $ 37.75万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942253
• 关键词: SDS polyacrylamide gel electrophoresis; age difference; cell membrane; gel mobility shift assay; high performance liquid chromatography; human tissue; immunocytochemistry; immunoprecipitation; ion exchange chromatography; liquid chromatography mass spectrometry; macular degeneration; mass spectrometry; matrix assisted laser desorption ionization; molecular pathology; oxidative stress; oxidized lipid; pathologic process; phospholipids; protein localization; protein structure function; proteomics; retinal pigment epithelium; western blottings

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular mechanisms of drusen formation and Bruch's membrane thickening in age-related macular degeneration (AMD). The unifying hypothesis is that protein modifications are causally involved in both processes. Drusen are extracellular deposits that form between the retinal pigment epithelium and Bruch's membrane and confluent drusen are the hallmark risk factor for developing AMD. The progression of AMO might be slowed or halted if drusen and Bruch's membrane changes can be modulated. The proposed research will identify proteins and lipids in drusen and Bruch's membrane from healthy and AMD donor tissues and characterize associated protein modifications and reactive lipid fragments. Four specific aims will test the following hypotheses: (i) that the drusen proteome differs among drusen sub-types; (ii) that the Bruch's membrane proteome varies with age and state of health; (iii) that lipid oxidation products in drusen and Bruch's membrane vary with age and state of health; (iv) that oxidative protein modifications contribute to drusen formation and Bruch's membrane thickening. Mass spectrometric methods will be used to identify and characterize proteins, phospholipids and lipid oxidation products. Immunocytochemistry will be used to confirm protein localization to drusen and Bruch's membrane. Western analyses, electrophoretic mobility shifts and bioinformatic tools will be used to detect protein modifications. The results will help establish a firm link between oxidative damage and the pathogenesis of AMD and provide new opportunities for developing strategies and therapies for preventing or limiting the complications of AMD.

描述（由申请人提供）：这项研究的长期目标是了解Drusen形成的分子机制和与年龄相关的黄斑变性（AMD）中Bruch膜增厚的分子机制。统一的假设是蛋白质修饰在两个过程中都与因果关系涉及。 drusen是视网膜色素上皮和Bruch膜和汇合drusen之间形成的细胞外沉积物是发展AMD的标志风险因素。如果可以调节Drusen和Bruch的膜变化，则AMO的进展可能会减慢或停止。拟议的研究将从健康和AMD供体组织中鉴定出Drusen和Bruch膜中的蛋白质和脂质，并表征相关的蛋白质修饰和反应性脂质片段。四个具体目标将检验以下假设： （i）drusen蛋白质组在drusen子类型之间有所不同； （ii）Bruch的膜蛋白质组随着年龄和健康状况而变化； （iii）Drusen和Bruch膜中的脂质氧化产物随着年龄和健康状况而变化； （iv）氧化蛋白修饰有助于drusen的形成和Bruch的膜增厚。质谱方法将用于识别和表征蛋白质，磷脂和脂质氧化产物。免疫细胞化学将用于确认Drousen和Bruch膜的蛋白质定位。西方分析，电泳迁移率转移和生物信息学工具将用于检测蛋白质修饰。结果将有助于在氧化损伤和AMD的发病机理之间建立牢固的联系，并为制定防止或限制AMD并发症的策略和疗法提供新的机会。

项目成果

Preliminary quantitative proteomic characterization of glaucomatous rat retinal ganglion cells.

• DOI: 10.1016/j.exer.2010.04.004
• 发表时间: 2010-07
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Crabb, John W.;Yuan, Xianglin;Dvoriantchikova, Galina;Ivanov, Dmitry;Crabb, John S.;Shestopalov, Valery I.
• 通讯作者: Shestopalov, Valery I.

Carboxyethylpyrrole adducts, age-related macular degeneration and neovascularization.

• DOI: 10.1007/978-0-387-74904-4_30
• 发表时间: 2008
• 期刊: Advances in experimental medicine and biology
• 作者: K. Renganathan;Q. Ebrahem;A. Vasanji;X. Gu;Liang Lu;J. Sears;R. G. Salomon;B. Anand-Apte;J. Crabb

Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.

• DOI: 10.1074/mcp.m800453-mcp200
• 发表时间: 2009-06
• 期刊: Molecular & cellular proteomics : MCP
• 作者: Gu J;Pauer GJ;Yue X;Narendra U;Sturgill GM;Bena J;Gu X;Peachey NS;Salomon RG;Hagstrom SA;Crabb JW;Clinical Genomic and Proteomic AMD Study Group
• 通讯作者: Clinical Genomic and Proteomic AMD Study Group

iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors.

• DOI: 10.1371/journal.pone.0135543
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Crabb JW;Hu B;Crabb JS;Triozzi P;Saunthararajah Y;Tubbs R;Singh AD
• 通讯作者: Singh AD