International Research Fellowship Program: Relationship of Human p53 and Rb Pathways to the Alternative Lengthening of Telomeres Phenotype

[6009 . 09] cesare国际研究奖学金计划使美国科学家和工程师能够在国外进行9至24个月的研究。该计划的奖励为联合研究提供了机会，并利用独特或互补的设施、专业知识和国外的实验条件。该奖项将支持Anthony J. Cesare博士与Roger R. Reddel博士在澳大利亚悉尼儿童医学研究所开展为期24个月的研究。端粒是保护真核生物染色体末端的蛋白质- dna帽。在人类细胞中，由于连续的细胞分裂，端粒缩短导致端粒结构功能障碍，并激活称为复制性衰老（RS）的细胞周期永久停滞状态。通过几种方法中的任何一种绕过RS都可以使细胞继续分裂，直到端粒完全被侵蚀，导致细胞危机并最终死亡。极少情况下，细胞通过再生和维持它们的端粒而免于死亡。当这种情况发生时，细胞达到永生状态，这对人类是潜在的有害的。人类细胞维持端粒的一种方式是通过一种鲜为人知的机制，即端粒的选择性延长（ALT）。最近的数据表明，alt阳性细胞具有永久性的、低水平的端粒功能障碍，这可能引发健康细胞中的RS。此外，这种功能障碍似乎是ALT机制的必要组成部分。本研究的目的是更好地了解介导对功能失调端粒反应的细胞通路在ALT中所起的作用。为了实现这些结果，PI将追求两个具体目标。第一个是对端粒功能障碍反应的中心介质，p53和视网膜母细胞瘤（Rb）基因的alt阳性细胞的研究。在ALT细胞系中，这些基因通常发生突变，或者它们的蛋白产物以其他方式失活。PI将确定这些成分是否具有ALT抑制功能，从而使其失活对ALT表型至关重要。其次，PI将调查ALT细胞端粒功能障碍的程度，以确定它是否足以在端粒引发DNA损伤反应。CMRI的癌症研究小组发现了ALT，并且仍然是端粒生物学这方面的领域领导者。该项目在包括端粒生物学、ALT和细胞永生化在内的广泛领域具有重要的智力潜力。

0602009CesareThe International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-four-month research fellowship by Dr. Anthony J. Cesare to work with Dr. Roger R. Reddel at Children's Medical Research Institute in Sydney, Australia.Telomeres are the protein-DNA caps that protect eukaryotic chromosome termini. In human cells, telomere shortening due to successive cellular division results in telomere structural dysfunction and the activation of a permanent state of cell cycle arrest termed replicative senescence (RS). By-pass of RS by any of several means allows a cell to continue to divide until the telomeres become completely eroded, resulting in cell crisis and eventually death. Very rarely, cells escape death by regenerating and maintaining their telomeres. When this occurs, the cell achieves an immortalized state, which is potentially deleterious in humans. One way that human cells maintain their telomeres is through a poorly understood mechanism termed Alternative Lengthening of Telomeres (ALT). Recent data suggest that ALT-positive cells have perpetual, low-levels of telomere dysfunction that would trigger RS in healthy cells. Further, this dysfunction appears to be a necessary component of the ALT mechanism. The goal of this study is to better understand what role the cellular pathways that mediate the response to dysfunctional telomeres play in regard to ALT. To achieve these results the PI will pursue two specific aims. The first is an investigation in ALT-positive cells of the central mediators of telomere dysfunction response, the p53 and Retinoblastoma (Rb) genes. Typically these genes are mutated, or their protein products are otherwise inactivated, in ALT cell lines. The PI will determine if these components possess ALT-inhibitory functions, thereby making their inactivation essential for the ALT phenotype. Second the PI will investigate the extent of telomere dysfunction in ALT cells to determine if it is sufficient to elicit a DNA damage response at the telomere. The Cancer Research Group at CMRI discovered ALT and remains the field leader in this aspect of telomere biology. This project has significant intellectual potential in a wide rage of fields including telomere biology, ALT and cellular immortalization.