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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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，这两种药物都是有效的抗癌机制。对致癌刺激作出反应而逃脱衰老或绕过凋亡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，有很好的证据表明，使突变失效、衰老和细胞凋亡有助于许多化疗药物的抗肿瘤活性，并且细胞凋亡可以导致多药耐药。芽殖酵母是研究后生动物细胞衰老和细胞死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体中的同源基因中被确定。这项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其哺乳动物对应系统的主要优势作为衰老的模型系统，因为酵母细胞代表着与衰老相关的过程，这是高等生物典型的，但衰老更快。酵母细胞更容易处理，因为它们会老化，并在几周内达到衰老。另一方面，哺乳动物细胞需要几个月的时间才能衰老，而哺乳动物生物的衰老需要几年，甚至几十年。鉴于不同物种的衰老和凋亡途径的显著保存，这一分析利用了与酵母系统相关的遗传工具和易用性，应该会进一步深入了解包括人类在内的高等生物中的类似过程。

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.