Stress-induced cell death mechanisms of fungi

应激诱导的真菌细胞死亡机制

基本信息

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
项目类别：
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

项目摘要

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：多细胞真菌中部分描绘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）。