Conservation of programmed cell death across species

跨物种程序性细胞死亡的保守性

• 批准号: 10640365
• 负责人: J. Marie Hardwick
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640365
• 关键词: Agriculture; Antifungal Agents; Apoptosis; Apoptotic; Aspergillosis; BCL2 gene; Biological Models; Biology; Candidiasis; Carrier Proteins; Cell Death; Cell Death Process; Cellular Stress; Cessation of life; Collection; Complex; Cryptococcosis; Cryptococcus neoformans; Drug resistance; Eukaryota; Evolution; Exhibits; Genes; Genetic study; Goals; Golgi Apparatus; Health; Homologous Gene; Hour; Human; Infection; Knock-out; Lysosomes; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Membrane; Modeling; Molecular; Molecular Genetics; Mucormycosis; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacology; Prokaryotic Cells; Proteins; Resistance; Role; Saccharomyces; Saccharomyces cerevisiae; Stress; Study models; Testing; Therapeutic; Vacuole; Virulence; Yeast Model System; Yeasts; cancer therapy; candidate identification; casein kinase; cell injury; environmental change; frontier; genome wide screen; global environment; in vitro Model; in vivo; inhibitor; knockout gene; novel; novel strategies; novel therapeutics; pathogen; resistant strain; theories

PROJECT SUMMARY Genetically regulated cell death processes are critical for maintenance of human health, defense against infection and for successful cancer therapy. In contrast, long-standing assumptions in biology and prevailing evolution theories have argued against the possibility that unicellular species encode intrinsic cell death pathways. However, a turning point has occurred in recent years with advancements in evolution theory and elegant molecular-genetic studies supporting the existence of genetically programmed/regulated cell death in unicellular species, best demonstrated in prokaryotes. However, less is known about cell death mechanisms in unicellular eukaryotes, including the well-studied model yeast Saccharomyces cerevisiae. Although many yeast genes have been implicated in promoting or inhibiting yeast cell death, the detailed mechanisms of cell death in unicellular eukaryotes are unresolved relative to well-studied mammalian cell death pathways, despite the relevance of pathogenic yeast such as Cryptococcus neoformans to human health, worsened by expanding drug resistance. Cryptococcosis is a worldwide concern and the US is not spared. Aspergillosis, mucormycosis and candidiasis are also problematic infections. The arsenal of anti-fungal agents is limited and new approaches are needed. Benefits of this project could extend to agricultural pathogens and global environmental changes. Yeast appear to have multiple unconventional cell death mechanisms. Whether these mechanisms were selected during evolution, or if they can be harnessed for therapeutic benefit analogous to new anti-cancer therapies is not yet known. Here we pursue these novel cell death pathways using a yeast model system and a pathogenic yeast to determine the role of cell death-resistance in pathogenesis.

项目总结 受基因调控的细胞死亡过程对维持人类健康至关重要，防御 感染和癌症治疗的成功。相比之下，生物学中长期存在的假设和流行 进化论反对单细胞物种编码固有细胞死亡的可能性 小路。然而，近年来，随着进化论的进步和 优雅的分子遗传学研究支持存在基因程序性/调节性细胞死亡 单细胞物种，在原核生物中表现最好。然而，对细胞死亡机制知之甚少。 单细胞真核生物，包括研究得很好的模型酵母酿酒酵母。虽然很多人 酵母基因涉及促进或抑制酵母细胞死亡，这是细胞的详细机制 相对于研究充分的哺乳动物细胞死亡途径，单细胞真核生物中的死亡仍未解决，尽管 致病酵母菌，如新生隐球菌，与人类健康的相关性，因 不断扩大的抗药性。隐球菌病是一个全球关注的问题，美国也不能幸免。曲霉病， 毛霉病和念珠菌病也是有问题的感染。抗真菌药物的武器库是有限的， 需要新的方法。该项目的好处可能扩展到农业病原体和全球 环境变化。酵母似乎有多种非常规的细胞死亡机制。不管是这些 机制是在进化过程中选择的，或者是否可以利用它们来实现类似于 新的抗癌疗法还不为人所知。在这里，我们使用酵母菌探索这些新的细胞死亡途径 模型系统和致病酵母菌，以确定细胞死亡抵抗在发病机制中的作用。