A Systems Approach to Stress Biology and Proteostasis Networks

应激生物学和蛋白质稳态网络的系统方法

• 批准号: 7890298
• 负责人: RICHARD I MORIMOTO
• 金额: $ 57.39万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890298
• 关键词: Acetylation; Acute; Afferent Neurons; Age; Aging; Animals; Biochemical Pathway; Biological; Biology; Cadmium; Caenorhabditis elegans; Cells; Cellular Stress; Chronic; Chronic stress; DNA Binding; Deacetylation; Development; Disease; Ensure; Failure; Functional disorder; Gene Expression; Gene Expression Profile; Gene Family; Genetic Screening; Goals; Health; Heat-Shock Response; Immune System Diseases; Individual; Lead; Life; Longevity; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Diseases; Molecular; Molecular Chaperones; Molecular Profiling; Nerve Degeneration; Neurons; Organism; Output; Pattern; Physiological; Post-Translational Protein Processing; Property; Proteins; Proteome; Quality Control; Regulation; Regulatory Pathway; Reporter; Role; Signal Pathway; Signal Transduction; Somatic Cell; Specificity; Stress; System; Technology; Tissues; Transgenic Organisms; Work; biological adaptation to stress; heat-shock factor 1; promoter; protein misfolding; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): The health of the proteome is of central importance to the cell and contributes significantly to the health and lifespan of the organism. The proteome is constantly challenged by external physiological and environmental stress, and places demands upon the protein quality control machinery and the proteostasis network, to sense and respond to the expression of misfolded and damaged proteins. It is increasingly clear that acute proteotoxicity, associated with the chronic expression of disease-associated aggregation-prone proteins, is daunting to the cell. When proteostatic capacity is exceeded, the consequence can be neurodegeneration, cancer, immunological disease, or metabolic diseases. Our studies have shown that expression of an aggregation-prone protein imbalances proteostasis and destabilize other conformationally challenged, metastable proteins. During ageing, the collapse of proteostasis leads to the disruption of multiple cellular activities leading to cell dysfunction and organismal failure. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact metazoan animal and the roles of stress-inducible transcription factors, HSF1 and Daf-16, to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease. We propose three integrated aims: (1) At the level of the organism, to understand how stress response's in the intact metazoan are regulated by specific neurons that sense and transmit environmental and physiological stress signals to control expression of chaperones in somatic cells. We will identify the signaling pathways that transmit the thermosensory signal from the AFD neurons to regulate the cell non-autonomous control of the heat shock response and HSF1 activity in somatic cells, (2) At the cellular level, to characterize the tissue-specific expression of the family of genes encoding molecular chaperones to elucidate the underlying strategy for chaperone networks in response to stress, during development, and ageing. These studies will provide a network-level understanding of the organizational properties of the eukaryotic chaperome, and (3) At the molecular level, to characterize the regulation of HSF1 by stress-inducible acetylation and deacetylation by the NAD-dependent sirtuin, SIRT1, and the role(s) of this post-translational regulatory pathway in metabolic control of cell stress and lifespan. PUBLIC HEALTH RELEVANCE: Chaperone networks and cytoprotective stress responses regulate the stability of the proteome, and consequently the health of the cell, and lifespan of the organism. An understanding of how these networks are organized and regulated has relevance to a multitude of diseases associated with protein misfolding and aggregation. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact animal and the roles of stress-inducible transcription factors to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease.

描述（由申请人提供）：蛋白质组的健康对细胞至关重要，并对生物体的健康和寿命有重要贡献。蛋白质组不断受到外部生理和环境压力的挑战，并对蛋白质质量控制机制和蛋白质稳定网络提出要求，以感知和响应错误折叠和受损蛋白质的表达。越来越清楚的是，与疾病相关的聚集倾向蛋白的慢性表达相关的急性蛋白毒性对细胞是令人生畏的。当超过蛋白质抑制能力时，后果可能是神经变性、癌症、免疫性疾病或代谢性疾病。我们的研究表明，一个聚集倾向的蛋白质的表达不平衡蛋白质稳定和不稳定的其他构象挑战，亚稳态蛋白质。在衰老过程中，蛋白质稳态的崩溃导致多种细胞活动的破坏，从而导致细胞功能障碍和有机体衰竭。这里提出的研究是为了了解不同的压力信号是如何被完整的后生动物中的单个细胞和组织所感知的，以及压力诱导转录因子HSF 1和Daf-16的作用，以整合压力生物学来增强细胞保护网络，从而抑制衰老和疾病的有害后果。我们提出了三个综合目标：（1）在生物体水平上，了解完整后生动物的应激反应是如何通过特定的神经元来调节的，这些神经元感知并传递环境和生理应激信号，以控制体细胞中伴侣蛋白的表达。我们将确定从AFD神经元传递热感觉信号以调节体细胞中热休克反应和HSF 1活性的细胞非自主控制的信号通路。（2）在细胞水平上，表征编码分子伴侣的基因家族的组织特异性表达，以阐明分子伴侣网络在应激、发育和衰老过程中的潜在策略。这些研究将提供一个网络水平的真核生物分子伴侣组的组织特性的理解，（3）在分子水平上，表征HSF 1的调控应激诱导的乙酰化和脱乙酰化的NAD依赖性sirtuin，SIRT 1，和（S）的作用，这种翻译后的调节途径在细胞应激和寿命的代谢控制。 公共卫生相关性：伴侣网络和细胞保护应激反应调节蛋白质组的稳定性，从而调节细胞的健康和生物体的寿命。了解这些网络是如何组织和调节的，与蛋白质错误折叠和聚集相关的许多疾病有关。本文提出的研究旨在了解完整动物个体细胞和组织如何感知不同的应激信号，以及应激诱导转录因子整合应激生物学以增强细胞保护网络的作用，从而抑制衰老和疾病的有害后果。