Heat Shock Transcription Factor Function and Regulation

描述（由申请人提供）： 所有生物体和细胞都暴露于应激条件下，无论是环境温度升高还是有毒化合物的结果，响应于通过正常线粒体呼吸、药理学试剂、感染和炎症、正常细胞生长和分裂或其他生理或病理生理条件产生的活性氧。 暴露于压力导致细胞周期的扰动，基因表达和细胞稳态控制的戏剧性重编程，以及蛋白质的解折叠和沉积。 不能产生适当的应激反应与中风和缺血-再灌注损伤、癌症、衰老、生物体生长、发育缺陷、不育和以蛋白质聚集和沉积为特征的神经变性疾病有关。 真核细胞通过诱导热休克蛋白（Hsps）的合成来响应应激条件，热休克蛋白在蛋白质折叠、运输、降解以及信号转导蛋白和转录因子的成熟和活化中起作用。在本申请中，我们概述了热休克转录因子（HSFs），从酵母到人类保守的应激反应转录因子诱导热休克蛋白表达的研究。 首先，阐明哺乳动物HSF 1感受应激的机制。其次，将确定调节哺乳动物HSF 1应激激活的细胞因子，并确定其作用机制。 第三，将进行酵母HSF靶基因的全基因组鉴定。酵母HSF靶基因调控网络将被分析为理解广泛的生物学意义的HSF应激反应的范例，这些研究将外推到哺乳动物HSF 1靶基因的识别。 Hsps的功能是保护生物体免受中风和缺血再灌注损伤，并且HSF 1的活化已显示出抑制蛋白质聚集，类似于在神经退行性疾病中发现的蛋白质聚集。 因此，了解HSF 1如何感知和响应压力，以及在压力下激活的靶基因，对我们的研究具有重要意义。

DESCRIPTION (provided by applicant): All organisms and cells are exposed to stressful conditions, whether a consequence of elevations in environmental temperatures or toxic compounds, in response to reactive oxygen species generated through normal mitochondrial respiration, pharmacological agents, infection and inflammation, normal cell growth and division or other physiological or pathophysiological conditions. Exposure to stress results in perturbations in the cell cycle, dramatic reprogramming of gene expression and cellular homeostatic controls and in the unfolding and deposition of proteins. The inability to mount appropriate stress responses is associated with stroke and ischemia-reperfusion injury, cancer, aging, defects in organismal growth, development, infertility and in neurodegenerative diseases characterized by protein aggregation and deposition. Eukaryotic cells respond to stress conditions by inducing the synthesis of heat shock proteins (Hsps), which function in protein folding, trafficking, degradation and in the maturation and activation of signal transduction proteins and transcription factors. In this application we outline studies on the induction of Hsp expression by Heat Shock Transcription Factors (HSFs), stress-responsive transcription factors conserved from yeast to humans. First, the mechanisms by which mammalian HSF1 senses stress will be elucidated. Secondly, cellular factors that modulate mammalian HSF1 stress activation will be identified and their mechanisms of action ascertained. Third, a genome wide identification of yeast HSF target genes will be carried out. Yeast HSF target gene regulatory networks will be analyzed as a paradigm for understanding the broad biological significance of the HSF stress response, and these studies will be extrapolated to the identification of mammalian HSF1 target genes. Hsps function to protect organisms from stroke and ischemia reperfusion injury, and activation of HSF1 has been shown to suppress protein aggregation similar to that found in neurodegenerative disease. Therefore, understanding how HSF1 senses and responds to stress, and the target genes activated during stress, have important