REGULATION OF HEAT SHOCK FACTOR BY HSBP1

热休克蛋白（hsps）在应激反应中迅速产生。 它们在细胞中起作用，以帮助正确的蛋白质折叠和易位，并防止不适当的蛋白质聚集。 错误折叠蛋白质的积累是蛋白质折叠疾病的核心，包括镰状细胞血红蛋白、囊性纤维化和朊病毒疾病，以及多因素疾病，如细菌和病毒感染、心肌缺血、神经变性疾病和癌症。热休克因子1（HSF 1）是热休克蛋白的主要应激反应转录激活因子。 热休克结合蛋白1（HSBP 1）与HSF 1相互作用，并通过未知的机制负调控其活性。 HSF 1和HSBP 1之间的相互作用负调控HSF 1的转录活性。 这种关联介导了HSF 1激活和衰减的多相过程中至少一个步骤的变化。 本研究拟探讨HSBP 1调控HSF 1活性的机制。 通过HSBP 1的过表达和HSBP 1显性失活突变体的表达，将确定HSBP 1对HSF 1激活/减弱的个体特征的影响。 此外，将通过随机诱变研究来研究HSBP 1的结构/功能关系。 我们还建议确定HSBP 1调节HSF 1的时间和空间关系，以便提出一个模型，在细胞应激反应过程中的蛋白质稳态的调节。

Heat shock proteins (hsps) are rapidly produced at high levels in response to stress. They function in the cell to aid in proper protein folding and translocation and to prevent inappropriate protein aggregation. The accumulation of misfolded proteins is central to diseases of protein folding, including sickle cell haemoglobin, cystic fibrosis and prion diseases, in addition to multifactorial diseases such as bacterial and viral infections, myocardial ischaemia, neurodegenerative diseases and cancer. Heat shock factor 1 (HSF1) is the major stress-responsive transcriptional activator of heat shock proteins. Heat shock binding protein 1 (HSBP1) interacts with HSF1 and negatively regulates its activity through an unknown mechanism. The interaction between HSF1 and HSBP1 negatively regulates HSF1 transcriptional activity. This association mediates a change in at least one step of the multiphase process of HSF1 activation and attenuation. The proposed research plan is to determine the mechanism of HSBP1 regulation of HSF1 activity. By the overexpression of HSBP1 and the expression of a dominant negative mutant of HSBP1, the affect of HSBP1 on individual characteristics of HSF1 activation/attenuation will be determined. In addition, the structure/function relationship of HSBP1 will be investigated by random mutagenesis studies. We also propose determining the temporal and spatial relationship of the HSBP1 regulation of HSF1 in order to propose a model for the regulation of protein homeostasis during the cellular stress response.