Sensing Protein Folding Capacity in the Cell During Aging

描述(由申请人提供)：这项GO拨款解决了开发生物传感器的关键需求，该传感器可以检测衰老过程中的蛋白质功能障碍。所有细胞的长期健康与蛋白质折叠和功能的可持续性密不可分。这是通过蛋白质稳态或‘蛋白质稳定’来实现的(Balch等人。(2008)Science 319：916)，一个复杂的分子相互作用网络，它决定了蛋白质组的健康。蛋白质平衡平衡蛋白质的生物合成、折叠、转位、组装/拆解和清除，以及环境或生理应激造成的挑战，导致细胞必须处理的错误折叠和受损蛋白质的持续流动。这种失衡，如果任其发展，可能会对细胞造成严重的分子损伤，导致关键组织的失调，导致病理，并易患上几乎所有的衰老疾病。适应和生存需要感知这些受损蛋白质的能力，并协调诱导保护性应激反应通路、伴侣和清除网络。尽管蛋白质平衡网络具有丰富和明显的能力来恢复折叠平衡，但细胞对慢性蛋白质毒性应激的适应能力似乎很差，例如在神经退行性衰老疾病中，当某些易于聚集的蛋白质表达时就会发生这种情况。我们假设，这种修复活动的下降，挑战蛋白质组的完整性，受到控制衰老的基因的强烈影响--从而将应激生物学、新陈代谢(饮食)和蛋白质动态平衡与健康和人类寿命联系起来。这项提议将斯克里普斯研究所的巴尔奇、凯利和怀斯曼实验室、索尔克研究所的迪林实验室和西北大学的森本实验室的互补优势结合在一起，开发和测试一套新的分子工具，该工具将在全球范围内报告蛋白质组在衰老过程中的健康状况。这些小组组成了蛋白质平衡老化传感器联盟(PASC)，以开发“蛋白质平衡传感器”，这是一种创新的分子记者，将提供对细胞每个隔室以及组织和生物模型中蛋白质折叠质量控制能力的实时评估。这些创新的探测器将评估影响人类寿命的蛋白质损伤、细胞应激、衰老和蛋白质构象疾病的后果。这些研究对衰老领域的影响非常广泛，涉及生物学和医学的所有领域。PASC成员的联合合作努力将利用蛋白质动态平衡和衰老方面的工具、技术和知识来测量细胞和动物内的折叠环境，并提供下一代工具，这些工具将大大加快老龄科学的努力。 公共卫生相关性：尽管环境和/或生理压力带来了许多挑战，但人类在老龄化期间的长期健康与蛋白质折叠和蛋白质功能的可持续性密不可分。长寿需要有能力感知受损的蛋白质，并协调诱导保护通路和清除网络，以响应控制衰老、应激生物学和新陈代谢(饮食)的基因。由Balch-Dlin-Kelly-Morimoto-Wiseman小组组成的蛋白质稳定性衰老传感器联盟(PASC)的这项提案将开发和测试一套新的创新分子工具，称为蛋白质稳定性传感器，它将在全球范围内实时报告人类蛋白质组在衰老过程中的健康状况。这些研究对老龄化领域的影响必然是非常广泛的，涉及与人类健康有关的生物学和医学的所有领域。

DESCRIPTION (provided by applicant): This GO grant addresses the critical need for development of biosensors that detect protein dysfunction during aging. The long-term health of all cells is inextricably linked to protein folding and sustainability of function. This is achieved by protein homeostatasis or 'proteostasis' (Balch et al. (2008) Science 319: 916), a complex network of molecular interactions that determines the health of the proteome. Proteostasis balances protein biosynthesis, folding, translocation, assembly/disassembly and clearance with the challenges imposed by environmental or physiological stress that results in a continual flux of misfolded and damaged proteins that the cell must manage. An imbalance, if left unattended can result in severe molecular damage to the cell, dysregulation of key tissues leading to pathology, and susceptibility to nearly all of diseases of aging. Adaptation and survival requires an ability to sense these damaged proteins and to coordinate induction of protective stress response pathways, chaperone and clearance networks. Despite the abundance and apparent capacity of the proteostasis network to restore the folding equilibrium, the cell appears to be poorly adapted for chronic proteotoxic stress as occurs when certain aggregation-prone proteins are expressed, for instance, in neurodegenerative aging diseases. We have hypothesized that this decline in repair activities, that challenges the integrity of the proteome, is influenced strongly by genes that control aging- thus linking stress biology, metabolism (diet), and protein homeostasis with health and human lifespan. The proposal brings together the complementary strengths of the Balch, Kelly and Wiseman laboratories at The Scripps Research Institute, the Dillin laboratory at the Salk Institute and the Morimoto laboratory at Northwestern University, to develop and test a new set of molecular tools that will globally report on the health of the proteome during aging. These groups form the Proteostasis Aging Sensor Consortium (PASC) to develop 'proteostasis sensors", innovative molecular reporters that will provide real- time assessment of the capabilities of protein folding quality control in each compartment of the cell, and in tissue and organismal models. These innovative probes will assess the consequences of protein damage, cell stress, aging and diseases of protein conformation that influence human longevity. The impact of these studies on the aging field is very broad and extends across all areas of biology and medicine. The combined collaborative efforts from the members of the PASC will leverage the tools, techniques and knowledge of protein homeostasis and aging to gauge the folding environment within cells and animals, and provide the next generation tools that will considerably accelerate efforts in the aging sciences. PUBLIC HEALTH RELEVANCE: The long-term health of mankind during aging is inextricably linked to protein folding and sustainability of protein function in spite of the many challenges imposed by environmental and/or physiological stress. Longevity requires an ability to sense damaged proteins and to coordinate induction of protective pathways and clearance networks responsive to genes that control aging, stress biology and metabolism (diet). This proposal by the Proteostasis Aging Sensor Consortium (PASC) consisting of the Balch-Dillin-Kelly-Morimoto- Wiseman groups will develop and test a new set of innovative molecular tools, referred to as proteostasis sensors that will globally report in real-time on the health of the human proteome during aging. The impact of these studies on the aging field is necessarily very broad and extends across all areas of biology and medicine related to human health.