A Systems Approach to Stress Biology and Proteostasis Networks

描述(由申请人提供)：蛋白质组的健康对细胞至关重要，对生物体的健康和寿命有很大贡献。蛋白质组不断受到外界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平衡网络提出了要求，以感知和响应错误折叠和损伤的蛋白质的表达。越来越明显的是，与疾病相关聚集倾向蛋白的长期表达相关的急性蛋白毒性对细胞来说令人望而生畏。当超过蛋白抑制能力时，结果可能是神经变性、癌症、免疫性疾病或代谢性疾病。我们的研究表明，一种易于聚集的蛋白质的表达会扰乱蛋白质平衡，并破坏其他构象挑战的亚稳态蛋白质的稳定。在衰老过程中，蛋白质平衡的崩溃导致多种细胞活动的中断，导致细胞功能障碍和机体衰竭。这里提出的研究是为了了解在完整的后生动物中，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HSF1和Daf-16的作用，以整合应激生物学，增强细胞保护网络，抑制衰老和疾病的有害后果。我们提出了三个综合的目标：(1)在生物体水平上，了解特定神经元如何调节完整后生动物的应激反应，这些神经元感知和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的信号通路，以调节细胞对体细胞热休克反应和HSF1活性的非自主控制；(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，以阐明伴侣网络应对压力、发育和衰老的潜在策略。这些研究将提供对真核生物伴侣组组织性质的网络水平的了解，以及(3)在分子水平上，表征HSF1通过依赖NAD的sirtuin SIRT1应激诱导的乙酰化和去乙酰化的调节，以及这一翻译后调节途径在细胞应激和寿命的代谢控制中的作用(S)。 公共卫生相关性：伴侣网络和细胞保护性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多种疾病有关。这里提出的研究是为了了解完整动物的单个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在整合应激生物学以增强抑制衰老和疾病有害后果的细胞保护网络中的作用。

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.