Drosophila Telomere Function

描述(申请人提供)：人类体细胞中端粒DNA的丢失，由于缺乏端粒酶表达而引起，导致细胞衰老，并与衰老有关。避免端粒丢失的正常后果是癌症进展的关键一步。因此，了解细胞对端粒丢失的正常反应机制以及绕过正常反应的机制对于理解并可能治疗与衰老相关的癌症和疾病非常重要。这项工作将使用模式生物黑腹果蝇来研究这些问题。初步实验表明，果蝇细胞对端粒丢失的反应与人类细胞对端粒丢失的反应非常相似，可能具有很高的信息量。这项工作有四个主要目标。第一个目标是定量描述果蝇体细胞对单个端粒丢失的反应。为此，将实施一种跟踪丢失端粒的细胞命运的方法。其次，将研究这些反应的遗传控制。第三个目标是确定雄性生殖系细胞的反应机制，在这种反应中，非端粒染色体末端得到有效修复。最终目标是研究修复后的染色体的性质，确定它们所拥有的端粒是否为染色体末端提供正常的保护功能，或者它们是否只具有部分功能。这些研究将提供对用于识别端粒丢失和指导细胞对这种丢失的反应的机制的理解。体细胞和生殖系细胞之间的差异可能会让我们深入了解在人类细胞中发现的类似差异。

DESCRIPTION (provided by applicant): The loss of telomeric DNA in human somatic cells, arising from of the lack of telomerase expression, causes cellular senescesce and is associated with aging. Escaping the normal consequences of telomere loss is a critical step in the progression of cancer. Thus, understanding the normal mechanisms of cellular response to telomere loss and mechanisms that bypass the normal response are important for understanding, and possibly treating, cancer and ailments associated with aging. This work will use the model organism Drosophila melanogaster to investigate these issues. Preliminary experiments show that the response of Drosophila cells to telomere loss is very similar of the response of human cells to telomere loss, and is likely to be highly informative. There are 4 primary goals of this work. The first goal is to quantitatively characterize the response of Drosophila somatic cells to loss of a single telomere. A method for tracking the fate of cells that have lost a telomere will be implemented for this purpose. Second, the genetic control of these responses will be investigated. The third goal is to determine the mechanism of response of male germline cells, in which the non-telomeric chromosome ends are efficiently healed. The final goal is to investigate the nature of the healed chromosomes, to determine whether the telomeres they posses provide a normal protective function to the end of the chromosomes, or whether they are only partially functional. These investigations will provide an understanding of the machinery used to recognize telomere loss and to direct the response of cells to such loss. The differences between somatic and germline cells may provide insight into similar differences found in human cells.