Microtuble-dependent markers for chromosome instability

描述（由申请人提供）：染色体不稳定性将癌症驱动到非整倍体状态，而非整倍体又被认为驱动导致肿瘤发生的突变。该项目的总体目标是了解微管动力学的改变如何导致染色体不稳定。具体来说，我们有初步的数据表明，微管聚合速率的增加，作为微管动力学调节变化的读数，与染色体不稳定性相关。此外，基于已建立的信号通路，导致微管动力学增加的病变并不总是可预测的。我们已经开发了一个相对简单的视觉检测病变，导致微管聚合率增加。我们还发现，微管聚合速率可以通过调节分子的实验改变而恢复到正常水平，其中一些已知是由小分子抑制剂控制的。我们假设，由微管动力学变化引起的染色体不稳定性代表了肿瘤改变的一个亚类，可能对某些类型的治疗有优先反应。我们的方法是筛选那些丢失导致微管聚合速率增加的基因。这些筛查将在华盛顿大学的奎洛斯高通量筛查中心进行。最初，我们将使用已建立的转化细胞系作为染色体不稳定性的模型系统，因为它稳定地保持一致的倍性。然后我们将确认对人类原代细胞的撞击。这些基因将成为治疗药物的良好候选基因。最后，在华盛顿大学干细胞和再生医学研究所的Quellos高通量筛选核心中，使用ChemBridge公司的115,000个小分子库筛选复归物，可能会发现新的治疗方法。

DESCRIPTION (provided by applicant): Chromosome instability drives cancers to a state of aneuploidy which, in turn, is thought to drive mutations that lead to tumorigenesis. The broad goal of this project is to understand how alterations in microtubule dynamics lead to chromosome instability. Specifically, we have preliminary data indicating that increased microtubule polymerization rates, which serve as a readout for changes in regulation of microtubule dynamics, are correlated with chromosome instability. Furthermore, the lesions that result in increased microtubule dynamics are not always predictable based on established signaling pathways. We have developed a relatively simple visual assay for lesions that lead to increased microtubule polymerization rates. We have also found that microtubule polymerization rates can be rescued and restored to normal levels by experimental alterations in regulatory molecules, some of which are known to be manageable by small molecule inhibitors. We hypothesize that chromosome instability deriving from changes in microtubule dynamics represents a subclass of neoplastic alterations that could be preferentially responsive to certain classes of therapeutics. Our approach is to screen for genes whose loss leads to increased microtubule polymerization rates. The screens will be performed at the Quellos High Throughput Screening Core at the University of Washington. Initially we will use an established transformed cell line which serves as a model system for chromosome instability because it stably maintains a consistent ploidy. We will then confirm hits in primary human cells. These genes will represent good candidates for therapeutic drugs. Finally, new therapies may be discovered by screening for revertants using the ChemBridge corporation library of 115,000 small molecules available at the Quellos High Throughput Screening Core at the Institute for Stem Cell and Regenerative Medicine at the University of Washington.