KU COMPLEX AND TELOMERE END PROTECTION

作为一名儿科肿瘤学家，我对新的靶点有着浓厚的兴趣 与癌症相关的治疗。我对端粒生物学的兴趣源于 一项重要的研究表明，端粒是中枢 对永生化和肿瘤形成过程的重要性。 在酵母中的实验，以及最近在人类细胞系中的实验，都坚定地证明了 建立了端粒长度和寿命之间的因果联系。 此外，大多数肿瘤表现出端粒酶的激活， 提出了端粒酶是否可以被开发为一种 化疗靶点。然而，最近的其他研究表明， 端粒酶阴性MISE可形成肿瘤，肿瘤细胞 细胞系可以利用端粒酶不依赖的途径形成端粒 维护，从而突出了彻底 如果考虑引入端粒动力学，则理解端粒动力学 抗端粒酶药物进入临床领域。这项建议的目的是 促进我们对端粒生物学的理解 Ku络合物和蛋白质两种活性的表征 CDC13P，它们似乎在调节端粒功能中发挥作用 保护染色体末端。这些研究将在 酵母菌，已被证明是一种有价值的快速 可外推的基因的识别和评估 研究人类的端粒生物学。Ku杂二聚体，以前 其在双标准DNA断裂修复和V(D)J中的作用 在哺乳动物细胞中的重组，也被证明在 酵母菌的端粒维持和染色质结构。古典主义 将利用遗传学来鉴定和分析KU中的突变 具有解偶联端粒和DNA修复功能的复合体。这些 然后将利用突变体来鉴定潜在的新蛋白质，这些蛋白质 在端粒维持过程中与Ku异源二聚体相互作用。新来的辜朝明 已鉴定的Ku相关蛋白和cdc13p将进一步分析 它们在体内与端粒染色质的联系以及它们如何 联想受到不同遗传背景的影响。 此外，这些蛋白质在调节末端的作用 端粒结构，即G-尾，将被研究。这些研究，在 解决端粒末端保护中的重要问题的附加TP， 将为我在古典遗传学和现代遗传学方面提供坚实的基础 分子生物学，以此为基础在分子肿瘤学方面建立事业。Dr。 伦德布莱德在分子和人类遗传学系的实验室 在贝勒医学院提供了一个极好的环境 用来培养我的科学技能。

As a pediatric oncologist, I have an intense interest in novel targets for cancer-related therapy. My interest in telomere biology arises from a significant body of work that indicates telomeres are of central importance to the processes of immortalization and tumorigenesis. Experiments in yeast, and recently in human cell lines, have firmly established a causal link between telomere length and lifespan. Furthermore, a majority of tumors exhibit activation of telomerase, raising the question whether telomerase can be exploited as a chemotherapeutic target. Other recent studies, however, have shown that telomerase-negative mise are capable of forming tumors, and tumor cell lines can utilize telomerase-independent pathways for telomere maintenance, thereby highlighting the importance of a thorough understanding of telomere dynamics if considering the introduction of anti-telomerase agents into the clinical arena. The aim of this proposal is to advance our understanding of telomere biology by the characterization of two activities, the Ku complex and the protein Cdc13p, which appear to play a role in mediating the telomere function of protecting chromosomal ends. These studies will be performed in yeast, which has proven to be a valuable model system for the rapid identification and evaluation of genes which can be extrapolated to the study telomere biology in humans. The Ku heterodimer, previously characterized for its role in double-standard DNA break repair and V(D)J recombination in mammalian cells, has also been shown to play a role in telomere maintenance and chromatin structure in yeast. Classical genetics will be utilized to identify and analyze mutants in the Ku complex which have uncoupled telomere and DNA repair function. These mutants will then be exploited to identify potential new proteins which interact with the Ku heterodimer in telomere maintenance. Ku, the newly identified Ku-associated proteins and Cdc13p will be further analyzed for their in vivo association with telomeric chromatin and how their associations are affected by different genetic backgrounds. Additionally, the role of these proteins in the regulation the terminal telomere structure, the G-tail, will be investigated. These studies, in addition tp addressing important questions in telomere end protection, will provide me with a firm foundation in classical genetics and modern molecular biology on which to build a career in molecular oncology. Dr. Lundblad's laboratory in the Department of Molecular and Human Genetics at the Baylor College of Medicine provides an excellent environment in which to develop my scientific skills.