GENETIC AND MOLECULAR ANALYSIS OF AGING AND APOPTOSIS IN THE YEAST, SACCHAROMYCE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。细胞衰老和细胞凋亡是与人类疾病有关的两个过程。例如，现在很清楚，两者都是有效的抗癌机制。逃避衰老或绕过细胞凋亡以响应致癌刺激的细胞可以发生恶性转化。细胞逃避程序性细胞死亡的能力被称为“癌症的标志”。值得注意的是，有充分的证据表明，致残突变、衰老和细胞凋亡参与了许多化疗药物的抗肿瘤活性，细胞凋亡可导致多药耐药。酿酒酵母（Saccharomyces cerevisiae）是后生动物细胞衰老和细胞凋亡等复杂生理过程的有用模型。这两个过程的分子机制似乎是保守的，遗传决定因素已经在酵母和高等生物的同源物中被确定。本研究计划概述了几种遗传策略，以确定酵母中这两个过程之间的分子联系。它将利用酵母系统相对于哺乳动物系统作为衰老模型系统的主要优势，因为酵母细胞代表了与衰老相关的过程，这是高等生物的典型过程，但衰老得更快。酵母细胞更容易处理，因为它们会在几周内老化并衰老。另一方面，哺乳动物的细胞需要几个月的时间来经历衰老，而哺乳动物的生物体则需要几年甚至几十年的时间来衰老。考虑到不同物种的衰老和凋亡途径的显著保守性，这种利用遗传工具和与酵母系统相关的易于研究的分析，应该导致对包括人类在内的高等生物的类似过程的进一步了解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cellular aging and apoptosis are two processes that have been implicated in human disease. For instance, it is now clear that both are potent anti-cancer mechanisms. Cells that either escape senescence or bypass apoptosis in response to oncogenic stimuli can undergo malignant transformation. The ability of cells to evade programmed cell death has been called a "hallmark of cancer". Significantly, there is good evidence that disabling mutations senescence and apoptosis contribute to the anti-tumor activity of many chemotherapeutic drugs and that apoptosis can result in multi-drug resistance. The budding yeast Saccharomyces cerevisiae has served as a useful model for complex physiological processes of metazoan cells, including aging and apoptotic cell death. Molecular mechanisms of both these processes appear to be conserved and genetic determinants have been identified in yeast with orthologues in higher organisms. This research program outlines several genetic strategies to identify molecular links between these two processes in yeast. It will exploit the primary advantage of the yeast system over its mammalian counterpart as a model system for aging because yeast cells represent aging-related processes typical of higher organisms but age more quickly. Yeast cells are easier to work with because they age and reach senescence within a matter of weeks. Mammalian cells, on the other hand, take months to undergo senescence, while mammalian organisms take years, if not decades, to age. Given the remarkable conservation of the aging and apoptotic pathways across diverse species, this analysis, which takes advantage of the genetic tools and ease of study associated with the yeast system, should lead to further insights into the analogous processes in higher organisms including human beings.