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).

项目摘要 哺乳动物细胞中的分子细胞死亡途径正在被广泛研究。这些基因调控的 细胞死亡过程对于维持人类健康、抵抗感染和成功地进行免疫至关重要。 癌症治疗，但它们的失调是疾病病理学的基础。在划定 分子细节已经产生了成功的设计药物，现在进入临床，如维奈托克， 特异性靶向抗凋亡BCL 2以触发肿瘤细胞死亡。相比之下，类似的方法不是 可用于触发由人类病原体如真菌、细菌和 寄生虫，因为我们对基础生物学知之甚少。几乎完全不了解 死亡微生物细胞中的相关事件是令人惊讶的，因为它们作为人类病原体的重要性。比如说， 真菌病原体对公众健康构成越来越大的威胁，全世界每年夺去150万人的生命。的 一个长期存在的假设，即微生物细胞不编码这种内在的死亡途径， 朝着这个方向前进。然而，来自多个来源的新的严格证据强烈认为， 有利于，并在多细胞真菌部分划定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， 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，一个主要的公共卫生负担（目标2）。