Stress-induced cell death mechanisms of fungi

应激诱导的真菌细胞死亡机制

• 批准号: 9896588
• 负责人: J. Marie Hardwick
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896588
• 关键词: Aging; Animals; Apoptosis; Apoptotic; BAX gene; BCL2 gene; Bacteria; Binding; Biological; Biological Assay; Biological Process; Biology; CASP3 gene; Caenorhabditis elegans; Candida albicans; Caspase; Cell Death; Cell Death Process; Cell Differentiation process; Cell Survival; Cell Wall; Cells; Cessation of life; Clinic; Clinical; Communities; Complex; Cryptococcus neoformans; Designer Drugs; Disease; Drosophila genus; Drug resistance; Environment; Eukaryota; Event; Food Supply; Genes; Genetic Transcription; Health; Human; Infection; Infection Control; Knowledge; Laboratories; Life Cycle Stages; Magnaporthe; Maintenance; Malignant Neoplasms; Mammalian Cell; Mammals; Maps; Mediating; Membrane; Metabolic; Microbe; Microbial Biofilms; Mitochondria; Modeling; Molecular; Mothers; Parasites; Partner in relationship; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Plants; Process; Property; Protein Family; Proteins; Public Health; Regimen; Resistance; Role; Saccharomyces cerevisiae; Sea Urchins; Source; Stress; Structure; Technology; Testing; Tissues; Uncertainty; Vesicle; Virulence; Yeast Model System; Yeasts; anti-cancer therapeutic; body system; cancer therapy; cell suicide; combat; cytochrome c; expectation; falls; fungus; human pathogen; interest; microbial; neoplastic cell; novel; novel strategies; pathogen; pathogenic fungus; resistant strain; response; stem; trafficking

PROJECT SUMMARY Molecular cell death pathways are being extensively studied in mammalian cells. These genetically regulated cell death processes are critical for maintenance of human health, defense against infection and for successful cancer therapy, but their deregulation underlies disease pathology. Considerable progress towards delineating the molecular details has yielded successful designer drugs now entering the clinic, such as venetoclax that specifically targets anti-apoptotic BCL2 to trigger tumor cell death. In contrast, analogous approaches are not available for triggering intrinsic cell death pathways encoded by human pathogens such as fungi, bacteria and parasites because very little is known about the basic biology. The near complete lack of understanding of the relevant events in dying microbial cells is surprising given their importance as human pathogens. For example, fungal pathogens pose an increasing threat to public health, claiming 1.5 million lives annually worldwide. The long-standing assumption that microbial cells do not encode such intrinsic death pathways has delayed advancements in this direction. However, new rigorous evidence from multiple sources argues strongly in favor, and partially delineated death pathways in multi-cellular fungi provide additional compelling support. Here we propose to map the first molecularly defined death pathway in a single-cell fungal/yeast species, the laboratory workhorse Saccharomyces cerevisiae (Aim 1), and to initiate studies that extend this knowledge to a single-cell human fungal/yeast pathogen Cryptococcus neoformans, a major public health burden (Aim 2).

项目概要 哺乳动物细胞中的分子细胞死亡途径正在被广泛研究。这些基因调控 细胞死亡过程对于维持人类健康、防御感染和成功至关重要 癌症治疗，但它们的放松管制是疾病病理学的基础。划定方面取得重大进展 分子细节已经产生了成功的设计药物，现已进入临床，例如 Venetoclax 专门针对抗凋亡 BCL2 来触发肿瘤细胞死亡。相比之下，类似的方法并不 可用于触发由真菌、细菌等人类病原体编码的内在细胞死亡途径 寄生虫，因为人们对基本生物学知之甚少。对这个问题几乎完全缺乏了解 鉴于微生物细胞作为人类病原体的重要性，死亡微生物细胞中的相关事件令人惊讶。例如， 真菌病原体对公众健康构成越来越大的威胁，每年在全球夺走 150 万人的生命。这 长期以来关于微生物细胞不编码这种内在死亡途径的假设已经被推迟 朝这个方向的进展。然而，来自多个来源的新的严格证据有力地证明了这一点： 多细胞真菌的部分描述的死亡途径提供了额外的令人信服的支持。 在这里，我们建议绘制单细胞真菌/酵母物种中第一个分子定义的死亡途径，即 实验室主力酿酒酵母（目标 1），并启动研究将这一知识扩展到 单细胞人类真菌/酵母病原体新型隐球菌，是一个主要的公共卫生负担（目标 2）。