Stress-induced cell death mechanisms of fungi

项目总结 分子细胞死亡途径在哺乳动物细胞中得到了广泛的研究。这些受基因控制的 细胞死亡过程是维持人类健康、抵御感染和成功的关键 癌症治疗，但它们的放松管制是疾病病理的基础。在划定方面取得了相当大的进展 分子细节已经产生了成功的设计药物，现在正在进入临床，例如万乃馨 特异性靶向抗凋亡的BCL2，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编码的内在细胞死亡途径，如真菌、细菌和 寄生虫，因为人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令人惊讶，因为它们作为人类病原体具有重要意义。例如, 真菌病原体对公众健康构成越来越大的威胁，每年在全球范围内夺走150万人的生命。这个 微生物细胞不编码这种内在死亡途径的长期假设已经被推迟 在这个方向上的进步。然而，来自多个来源的新的严格证据有力地证明了 在多细胞真菌中，部分描述的死亡途径提供了额外的引人注目的支持。 在这里，我们建议在单细胞真菌/酵母物种中定位第一个分子定义的死亡途径，即 实验室的主力酿酒酵母(目标1)，并启动研究，将这一知识扩展到 单细胞人类真菌/酵母病原体新生隐球菌，一个主要的公共卫生负担(目标2)。

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).