Elucidating the Relations of Heat Shock Factors, Molecular Chaperones and Prions

描述(由申请人提供)：尽管数十年的科学研究和公众和政府对感染蛋白的潜在危险及其在流行病中的作用的担忧加剧，如新的变种克雅氏病、疯牛病和慢性消耗性疾病，但负责将正常细胞蛋白转化为传染性普里恩蛋白的机制仍然令人费解。导致蛋白构象变化的细胞因子，以及随后稳定改变的蛋白质构象所必需的因子，仍然是一个谜。考虑到Pron的形成和遗传与蛋白质折叠机制密切相关，我们建议研究Pron的形成和热休克转录因子(HSFs)之间的联系。HSFs是进化上保守的转录因子，负责大多数分子伴侣的生物合成，这些分子伴侣通过折叠或解聚应激产生的变性蛋白来保护细胞免受极端恶劣条件的影响。一些分子伴侣也被证明在Pron的繁殖中起着重要的作用。以发芽酵母酿酒酵母为模式生物，研究HSFs与Pron形成/繁殖的关系。我们建议的研究的长期目标是确定其功能受HSFs调控的蛋白质因子，这些蛋白质因子对Pron的形成/繁殖是必不可少的。其具体目的是：1)研究热休克蛋白90 kDa(Hsp90)复合体在从头形成和[PSI+]“品系”维持中的调节作用；2)检测HSF和Hsp90复合体是否调节其他酵母蛋白。我们将研究HSF和Hsp90/辅伴侣蛋白的作用是否具有[PSI+]特异性：3)确定作为HSF靶标的其他新因子，并负责Pron的形成和传播。公共卫生相关性：Pron病是一组传染性神经退行性疾病，也称为传染性海绵状脑病。目前，普恩病毒病因学的分子机制知之甚少。我们建议确定普恩蛋白构象转换所需的细胞因子，并对随后获得的普恩蛋白构象的稳定起重要作用。拟议中的研究的成功可能会为未来的药物发现和毁灭性的Pron疾病的新疗法提供目标基因。

DESCRIPTION (provided by applicant): Despite decades of scientific research and heightening public and governmental anxiety over the potential dangers of infectious proteins and their role in epidemics such as new variant Creutzfeldt-Jacob disease, Mad Cow disease, and chronic Wasting disease, the mechanisms responsible for the conversion of a normal cellular protein into an infectious prion protein continue to defy understanding. The cellular factors instrumental to the protein conformational changes that result in prion formation, as well as those factors necessary for the subsequent stabilization of the altered prion conformation, remain a mystery. Considering that prion formation and inheritance are tightly related to the protein folding machinery, we propose to investigate the link between prion formation and heat shock transcriptional factors (HSFs). HSFs are evolutionally conserved transcriptional factors responsible for the biosynthesis of the majority of molecular chaperones, which are essential for protecting cells from extreme harsh conditions by refolding or dis-aggregating denatured proteins produced during the stress. Several molecular chaperones are also shown to play essential roles in prion propagation. Using the budding yeast Saccharomyces cerevisiae as the model organism, we propose to elucidate the relationship between HSFs and prion formation/propagation. Our long-term goal of the proposed research is to identify protein factors whose functions are regulated by HSFs and are essential for prion formation/propagation. The specific aims are: 1) to examine the regulatory role of heat shock protein 90kDa (Hsp90) complex in de novo formation and "strain" maintenance of [PSI+]; 2) to test if HSF and Hsp90 complex regulate other yeast prions. We will investigate if the effects of HSF and Hsp90/cochaperones are [PSI+] specific: 3) to identify additional novel factors that are HSF targets and responsible for prion formation and propagation. PUBLIC HEALTH RELEVANCE: Prion diseases are a group of infectious neurodegenerative diseases also known as transmissible spongiform encephalopathies. The molecular mechanisms govern the etiology of prion diseases are poorly understood. We propose to identify cellular factors that are required for prion conformational conversion and are important for subsequent stabilization of the acquired prion conformation. The success of proposed study will likely provide target genes for future drug discovery and new therapeutics for the devastating prion diseases.