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.

项目概要 基因调控的细胞死亡过程对于维持人类健康、防御疾病至关重要 感染和成功的癌症治疗。相比之下，生物学中长期存在的假设和流行的 进化论反对单细胞物种编码内在细胞死亡的可能性 途径。然而，近年来，随着进化论和进化论的进步，出现了一个转折点。 优雅的分子遗传学研究支持基因编程/调节的细胞死亡的存在 单细胞物种，在原核生物中得到了最好的证明。然而，人们对细胞死亡机制知之甚少。 单细胞真核生物，包括经过充分研究的模型酵母酿酒酵母。虽然很多 酵母基因与促进或抑制酵母细胞死亡有关，细胞死亡的详细机制 相对于经过充分研究的哺乳动物细胞死亡途径，单细胞真核生物的死亡尚未得到解决，尽管 致病性酵母菌（例如新型隐球菌）与人类健康的相关性，因 扩大耐药性。隐球菌病是一个世界性的问题，美国也未能幸免。曲霉病， 毛霉菌病和念珠菌病也是有问题的感染。抗真菌药物的库是有限的 需要新的方法。该项目的好处可以扩展到农业病原体和全球 环境变化。酵母似乎具有多种非常规细胞死亡机制。无论是这些 机制是在进化过程中选择的，或者是否可以利用它们来获得类似于治疗的益处 新的抗癌疗法尚不清楚。在这里，我们使用酵母来探索这些新的细胞死亡途径 模型系统和致病酵母以确定细胞死亡抗性在发病机制中的作用。