Sensing Protein Folding Capacity in the Cell During Aging

描述（由申请人提供）：该GO资助解决了开发生物传感器的关键需求，该传感器可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“蛋白质稳态”（Balch et al.（2008）Science 319：916）实现的，蛋白质稳态是决定蛋白质组健康的分子相互作用的复杂网络。蛋白质稳态平衡蛋白质生物合成、折叠、易位、组装/拆卸和清除与环境或生理应激所施加的挑战，所述环境或生理应激导致细胞必须管理的错误折叠和受损蛋白质的持续流动。不平衡，如果不加注意，会导致细胞严重的分子损伤，导致病理学的关键组织失调，以及对几乎所有衰老疾病的易感性。适应和生存需要能够感知这些受损的蛋白质，并协调诱导保护性应激反应途径，伴侣和清除网络。尽管蛋白质稳态网络的丰度和恢复折叠平衡的明显能力，但细胞似乎对慢性蛋白毒性应激适应不良，例如在神经退行性衰老疾病中表达某些易于聚集的蛋白质时会发生这种情况。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-从而将压力生物学，代谢（饮食）和蛋白质稳态与健康和人类寿命联系起来。该提案汇集了Scripps研究所Balch，Kelly和Wiseman实验室，Salk研究所Dillin实验室和西北大学Morimoto实验室的互补优势，以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衰老过程中蛋白质组的健康状况。这些小组组成了蛋白质稳定老化传感器联盟（PASC），以开发“蛋白质稳定传感器”，创新的分子报告者，将提供真实的实时评估蛋白质折叠质量控制的能力，在每个隔室的细胞，组织和生物体模型。这些创新的探针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，并延伸到生物学和医学的所有领域。PASC成员的共同合作将利用蛋白质稳态和衰老的工具，技术和知识来衡量细胞和动物内的折叠环境，并提供下一代工具，这将大大加速衰老科学的努力。 公共卫生相关性：尽管环境和/或生理压力带来了许多挑战，但人类在衰老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，并协调对控制衰老、应激生物学和代谢（饮食）的基因作出反应的保护途径和清除网络的诱导。由Balch-Dillin-Kelly-Morimoto- Wiseman小组组成的Proteostasis Aging Sensor Consortium（PASC）的这一提案将开发和测试一套新的创新分子工具，称为Proteostasis传感器，该传感器将在全球范围内实时报告衰老期间人类蛋白质组的健康状况。这些研究对老龄化领域的影响必然非常广泛，并延伸到与人类健康相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.