Preprostaglandin Endoperoxides

前前列腺素内过氧化物

• 批准号: 8102238
• 负责人: Robert Gerd Salomon
• 金额: $ 25.76万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102238
• 关键词: Age related macular degeneration; Antibodies; Attention; Autoantibodies; Binding Proteins; Biochemistry; Biological; Biology; Blindness; Blocking Antibodies; Chemicals; Chemistry; Clinic; Collaborations; Commit; Cornea; Corneal Neovascularization; DNA Sequence Rearrangement; Detection; Disease; Early Diagnosis; Etiology; Exposure to; Eye; Eye diseases; Flowers; Foundations; Free Radicals; Generations; Glaucoma; Glean; Goals; Graft Rejection; Grant; Individual; Injury; Institutes; Intuition; Investigation; Keratitis; Knowledge; Learning; Lipid Biochemistry; Lipid Chemistry; Lipids; Logic; Mediating; Medicine; Methods; Molecular; Pathway interactions; Patients; Permeability; Pilot Projects; Post-Translational Protein Processing; Prevention approach; Primary Open Angle Glaucoma; Process; Proteins; Pyrroles; Reaction; Receptor Activation; Research; Research Personnel; Retina; Role; Severity of illness; Staging; Study models; Testing; Therapeutic Intervention; Toxin; Trabecular meshwork structure; Vitamin B6; adduct; age related; angiogenesis; arm; base; crosslink; in vitro Model; in vivo; insight; neovascularization; novel; novel strategies; novel therapeutic intervention; oxidation; oxidized lipid; prevent; programs; protein function; receptor; receptor binding; response

DESCRIPTION (provided by applicant): This grant renewal application focuses on understanding the role of lipid-based oxidative protein modification (oxPM) in the etiology of eye diseases. We postulate that oxPM can interfere with protein function or result in pathological receptor-mediated responses. The overarching questions are: (1) how are oxPM generated in vivo, (2) which proteins are modified, (3) what are the pathological consequences, and (4) what therapeutic interventions can prevent oxPM formation or block their receptor-mediated sequelae. Biological entities must adapt to the nonenzymatic reactions, such as free radical-induced lipid oxidation, to which biomolecules are prone. Understanding these proclivities is the cornerstone of our approach to unraveling the involvements of lipid oxidation in disease processes. Our studies have resulted in the identification of many new biologically active oxidized lipids, characterization of their reactions with proteins, and molecular level insights into the pathological consequences of this oxidative biochemistry. One approach, that has been especially productive for us, is to learn about the chemistry of lipid oxidation and the reactions of lipid oxidation products, follow by an investigation of the biological occurrence and consequences of that chemistry. Such studies led to our discoveries of levuglandins (LGs) and isolevuglandins (isoLGs), extremely reactive products of enzymatic and nonenzymatic lipid oxidation, respectively, that are generated through novel rearrangements of endoperoxide intermediates. Because they react within seconds with proteins, these stealthy toxins evaded detection in vivo. But armed with knowledge of their chemistry obtained from "model studies", we devised methods to detect their protein adducts. Their formation in vivo is now firmly established, and an understanding of their involvement in a host of disease processes is emerging. Our immediate goals for the next four years are to understand: (1) the role of LG and isoLG-based oxPM in the etiology of glaucoma and keratitis, and the utility of vitamin B6 for preventing their formation in vivo, (2) the involvements of carboxyalkyl pyrrole-modified proteins in age-related macular degeneration, choroidal and cornea! neovascularization, and (3) the utility of single-chain antibodies for blocking receptor-mediated pathological responses to oxPM. The understanding gleaned through these studies will provide new approaches to the prevention, early diagnosis, and treatment of eye diseases associated with oxidative injury.

描述（由申请人提供）：本资助续期申请的重点是了解基于脂质的氧化蛋白修饰（oxPM）在眼病病因学中的作用。我们假设oxPM可以干扰蛋白质功能或导致病理受体介导的反应。首要的问题是：(1)体内如何产生oxPM，(2)哪些蛋白质被修饰，(3)什么是病理后果，(4)什么样的治疗干预可以阻止oxPM形成或阻断其受体介导的后遗症。生物实体必须适应非酶反应，如自由基诱导的脂质氧化，这是生物分子容易发生的。了解这些倾向是我们解开脂质氧化在疾病过程中参与的方法的基石。我们的研究已经鉴定了许多新的生物活性氧化脂质，表征了它们与蛋白质的反应，并在分子水平上深入了解了这种氧化生物化学的病理后果。一种方法，对我们来说特别有效，就是学习脂质氧化的化学过程和脂质氧化产物的反应，然后研究这种化学过程的生物学过程和后果。这些研究导致我们发现左旋ugugandins （LGs）和异旋ugugandins (isoLGs)，分别是酶促和非酶促脂质氧化的极活性产物，它们是通过内过氧化物中间体的新重排产生的。因为它们在几秒钟内就能与蛋白质发生反应，这些隐形毒素在体内逃避了检测。但有了从“模型研究”中获得的化学知识，我们设计了检测它们的蛋白质加合物的方法。它们在体内的形成现在已经确定，并且对它们参与许多疾病过程的理解正在出现。我们未来四年的直接目标是了解：(1)LG和基于isolg的oxPM在青光眼和角膜炎的病因学中的作用，以及维生素B6在体内预防其形成的效用，(2)羧基烷基吡咯修饰蛋白在年龄相关性黄斑变性、脉络膜和角膜中的作用！(3)单链抗体在阻断受体介导的oxPM病理反应中的应用。通过这些研究收集的理解将为与氧化损伤相关的眼病的预防、早期诊断和治疗提供新的方法。