A Holistic Approach to Understanding Small Heat Shock Protein Mechanism

了解小热激蛋白机制的整体方法

• 批准号: 10398195
• 负责人: Rachel E Klevit
• 金额: $ 39.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398195
• 关键词: Age related macular degeneration; Aging; Belief; Blindness; Brain Hypoxia-Ischemia; Cataract; Cell Aging; Cells; Cellular Stress; Chimera organism; Chronic stress; Client; Complex; Comprehension; Cornea; Crystalline Lens; Crystallins; Data; Deuterium; Development; Diabetic Retinopathy; Disease; Exposure to; Failure; Genetic; Genetic Transcription; Goals; Grain; Grant; HSPB1 gene; Health; Heat shock proteins; Human; Hydrogen; Individual; Injury; Knowledge; Lead; Link; Maintenance; Mass Spectrum Analysis; Modeling; Modification; Molecular; Molecular Chaperones; Molecular Conformation; Mutation; N-terminal; Neurodegenerative Disorders; Ocular Pathology; Pathology; Phosphorylation; Physiological; Positioning Attribute; Proteins; Resolution; Rest; Retina; Smoking; Specificity; Stress; Structure; Surface; Techniques; Testing; Tissues; Ultraviolet Rays; crosslink; first responder; holistic approach; lens; lens transparency; novel; programs; protein aggregation; protein function; protein misfolding; protein structure function; response; tau Proteins; tau aggregation; unnatural amino acids; Age related macular degeneration; Aging; Belief; Blindness; Brain Hypoxia-Ischemia; Cataract; Cell Aging; Cells; Cellular Stress; Chimera organism; Chronic stress; Client; Complex; Comprehension; Cornea; Crystalline Lens; Crystallins; Data; Deuterium; Development; Diabetic Retinopathy; Disease; Exposure to; Failure; Genetic; Genetic Transcription; Goals; Grain; Grant; HSPB1 gene; Health; Heat shock proteins; Human; Hydrogen; Individual; Injury; Knowledge; Lead; Link; Maintenance; Mass Spectrum Analysis; Modeling; Modification; Molecular; Molecular Chaperones; Molecular Conformation; Mutation; N-terminal; Neurodegenerative Disorders; Ocular Pathology; Pathology; Phosphorylation; Physiological; Positioning Attribute; Proteins; Resolution; Rest; Retina; Smoking; Specificity; Stress; Structure; Surface; Techniques; Testing; Tissues; Ultraviolet Rays; crosslink; first responder; holistic approach; lens; lens transparency; novel; programs; protein aggregation; protein function; protein misfolding; protein structure function; response; tau Proteins; tau aggregation; unnatural amino acids

ABSTRACT/SUMMARY Cells have numerous strategies to cope with the consequences of stresses that cause protein misfolding and aggregation and lead to formation of plaques, fibrils, and other aggregated species encountered in aging cells, cataract, and neurodegenerative diseases. The protein chaperones known as small heat shock proteins are the cell’s first responders and are therefore key to maintenance of cellular health. Ocular tissues are subjected to stresses such as exposure to UV light, smoking, hypoxia, and ischemia. sHSP function is linked to three of the most prevalent ocular pathologies leading to blindness worldwide: cataract, age-related macular degeneration, and diabetic retinopathy which together account for 65% of world blindness. In lens, sHSPs perform the critical task of maintaining lens transparency and failure to do so is directly linked to cataract. sHSPs are expressed constitutively in retinal cells and are upregulated following injury or stress. Mechanisms used by sHSPs to delay the onset of aggregation of proteins remain enigmatic due to technical challenges posed by sHSPs and the aggregate-prone proteins they protect. Recent developments in the study of disordered proteins and breakthroughs made during the previous period of this long-standing project promise to overcome this critical barrier to mechanistic understanding. Techniques such as NMR, hydrogen-deuterium exchange/mass spectrometry, and covalent cross-linking/mass spectrometry can provide fine-grained information regarding disordered regions of sHSPs that have largely gone uncharacterized but are known to be essential for sHSP activity. The goal of this renewal application is to develop a holistic (“characterized by comprehension of the parts of something as intimately interconnected and explicable only by reference to the whole”) understanding of sHSP structure and function. The effects of stress conditions, modifications, and mutations will be assessed and interpreted in the context of the resultant novel models.

摘要/摘要 细胞有许多应对引起蛋白质的应力后果的策略 错误折叠和聚集，并导致斑块，原纤维和其他聚合的形成 在衰老细胞，白内障和神经退行性疾病中遇到的物种。蛋白质 被称为小热激蛋白的伴侣是细胞的第一个响应者，因此是 维持细胞健康的关键。眼组织受到应力，例如 暴露于紫外线，吸烟，缺氧和缺血。 SHSP功能链接到三个 大多数流行的眼病理学导致世界各地失明：白内障，与年龄有关的黄斑 变性和糖尿病性视网膜病，占世界失明的65％。在 镜头，shsps执行保持镜头透明度和未能执行的关键任务是 直接链接到白内障。 SHSP在永久性细胞中始终如一，为 受伤或压力后上调。 SHSP使用的机制延迟了 由于SHSP和SHSP提出的技术挑战，蛋白质的聚集仍然神秘 它们保护的总蛋白质。无序蛋白研究的最新发展 以及在这个长期项目的上一个期间的突破承诺 克服机械理解的关键障碍。 NMR等技术 氢 - 居民交换/质谱和共价交联/质量 光谱法可以提供有关SHSP无序区域的细粒度信息 在很大程度上没有表征，但已知对于SHSP活动至关重要。目标 这种更新的应用是为了开发整体（“以理解部分的理解为特征 仅通过参考整体而密切相互联系和明确的事物”） 了解SHSP结构和功能。压力条件，修改的影响， 并将在由此产生的新型模型的背景下评估和解释突变。