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

描述（由申请人提供）：尽管经过数十年的科学研究，公众和政府对传染性蛋白的潜在危险及其在诸如新型克雅氏病、疯牛病和慢性消耗性疾病等流行病中的作用越来越焦虑，但正常细胞蛋白转化为传染性朊病毒蛋白的机制仍然无法理解。导致朊病毒形成的蛋白质构象变化的细胞因素，以及随后稳定改变的朊病毒构象所必需的那些因素，仍然是一个谜。考虑到朊病毒的形成和遗传与蛋白质折叠机制密切相关，我们建议研究朊病毒的形成与热休克转录因子（hsf）之间的联系。hsf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，这些分子伴侣通过在逆境中产生的变性蛋白质的重新折叠或分解，对保护细胞免受极端恶劣条件的影响至关重要。一些分子伴侣也被证明在朊病毒繁殖中起重要作用。以出芽酵母酿酒酵母（Saccharomyces cerevisiae）为模型生物，探讨hsf与朊病毒形成/繁殖的关系。我们提出的研究的长期目标是确定功能受hsf调节的蛋白因子，这些蛋白因子对朊病毒的形成/繁殖至关重要。具体目的是：1)研究热休克蛋白90kDa （Hsp90）复合物在[PSI+]新生形成和“菌株”维持中的调节作用；2)检测HSF和Hsp90复合物是否调控其他酵母朊病毒。我们将研究HSF和Hsp90/cochaperones是否具有[PSI+]特异性：3)以确定HSF靶点和负责朊病毒形成和繁殖的其他新因子。公共卫生相关性：朊病毒疾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。控制朊病毒疾病病因的分子机制尚不清楚。我们建议确定朊病毒构象转换所需的细胞因子，并对随后获得的朊病毒构象的稳定很重要。该研究的成功将可能为未来的药物发现和治疗破坏性朊病毒疾病的新方法提供靶基因。

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.