Oxidative stresses and complex proteomic responses to them

氧化应激及其复杂的蛋白质组反应

• 批准号: 8552368
• 负责人: Stuart Maudsley
• 金额: $ 48.78万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552368
• 关键词: Affect; Aging; Alzheimer' s Disease; Cell physiology; Cells; Chronic; Complex; Data; Disease; Environment; Etiology; Exposure to; Genomics; Goals; Huntington Disease; Hyperoxia; Hypoxia; Investigation; Mediating; Metabolism; Molecular; Neuraxis; Neurodegenerative Disorders; Oxidative Stress; Oxygen; Oxygen measurement, partial pressure, arterial; Parkinson Disease; Pharmacology; Physiological; Proteomics; Reaction; Reactive Oxygen Species; Receptor Signaling; Research; Role; Signal Transduction; Stimulus; Stress; System; Time; Tissues; age related; cellular pathology; interest; oxidative damage; protein function; receptor; receptor-mediated signaling; response; therapeutic target

Summary For many of the major neurodegenerative disorders alteration of protein function and cell physiology by changes in oxygen availability or the presence of damaging oxygen radicals may underlie many of the deleterious effects of these diseases. Therefore a true in-depth understanding of how the oxidative environment affects cellular responses to protective or detrimental stimuli is of great importance. At this present time, we are only now, understanding that the modes in which we perform cell and receptor signaling investigation may be biased towards a non-physiological paradigm, i.e. investigating receptor pharmacology under atmospheric oxygen tensions. We are therefore initially undertaking a painstaking analysis first of how central nervous system tissue responds, at the genomic and proteomic level, to multiple oxygen tensions. Our results from this primary study will facilitate subsequent studies to identify how transmembrane receptor-mediated signaling paradigms, one of the most important therapeutic targets, act at these various tensions. It is highly likely, as we have seen with our preliminary data, that there are wholescale reactive genomic and proteomic cellular changes in response to altered oxygen tension environments. With these complex and widespread changes it is highly likely that receptor signaling systems may be affected and thus potentially alter the efficacy of pharmacotherapeutics. Our research will aim to generate pharmacotherapeutics that will counteract these deficits and therefore maintain pharmacological efficacy in a variety of pathophysiological or aging states.

概括 对于许多主要的神经退行性疾病，蛋白质功能和细胞生理的改变，通过氧气可用性的变化或损害氧自由基的存在可能是这些疾病的许多有害作用的基础。 因此，对氧化环境如何影响细胞对保护性或有害刺激的细胞反应的真正深入了解非常重要。 目前，我们直到现在，了解我们执行细胞和受体信号调查的模式可能会偏向非生理范式，即在大气氧张力下研究受体药理。 因此，首先，我们首先对中枢神经系统组织在基因组和蛋白质组学水平上如何应对多种氧气张力进行艰苦的分析。 这项主要研究的结果将有助于随后的研究，以确定跨膜受体介导的信号传导范例（最重要的治疗靶标之一）如何在这些各种张力下作用。 正如我们在初步数据中看到的那样，很有可能存在二大反应性基因组和蛋白质组学细胞变化，以响应改变的氧气张力环境。 随着这些复杂而广泛的变化，受体信号系统很可能会受到影响，从而有可能改变药物治疗的功效。 我们的研究将旨在产生药物治疗剂，以抵消这些缺陷，从而维持各种病理生理或衰老状态的药理功效。