Microtuble-dependent markers for chromosome instability

染色体不稳定的微管依赖性标记

基本信息

批准号：
8827718
负责人：
Linda Wordeman
金额：
$ 16.8万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8827718
关键词：
Adverse drug effect Affect Aneuploidy Antineoplastic Agents Appearance Behavior Biological Assay Biological Models Cell Death Cells Chromosomal Instability Chromosome Segregation Data Drug Targeting Exhibits Fibroblasts Genes Genetic Genetic Screening Genome Goals Health Human In Vitro Institutes Lead Lesion Libraries Malignant Neoplasms Measurable Microsatellite Instability Microtubule Polymerization Microtubules Mitotic spindle Molecular Profiling Mutation Oncogenic Paclitaxel Pathway interactions Pharmaceutical Preparations Phenotype Ploidies Polymers Process Reading Refractory Regenerative Medicine Regulation Resistance Shapes Signal Pathway Small Interfering RNA Specificity Stem cells Therapeutic Transformed Cell Line Tubular formation Tubulin Tumor Suppressor Genes Tumor Suppressor Proteins Universities Up-Regulation Visual Washington base beta Tubulin cancer cell cancer therapy cell type design dimer genetic regulatory protein high throughput screening inhibitor/antagonist monastrol neoplastic neoplastic cell novel penis foreskin pharmacophore screening small molecule targeted cancer therapy tumor tumor growth tumorigenesis

项目摘要

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.

描述（由申请人提供）：染色体不稳定性驱动器癌症癌症至一种非整倍性状态，而该状态又被认为驱动突变导致肿瘤发生。该项目的广泛目标是了解微管动力学的变化如何导致染色体不稳定性。具体而言，我们拥有初步数据，表明增加的微管聚合速率（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，根据已建立的信号通路，导致微管动力学增加的病变并不总是可预测的。我们为病变开发了一个相对简单的视觉测定，导致微管聚合速率增加。我们还发现，通过调节分子的实验改变可以挽救微管聚合速率，并将其恢复到正常水平，其中一些可以通过小分子抑制剂可控制。我们假设从微管动力学的变化中衍生出的染色体不稳定性代表了肿瘤变化的子类，可以优先响应某些类别的治疗剂。我们的方法是筛选其损失导致微管聚合速率增加的基因。屏幕将在华盛顿大学的Quellos高吞吐量筛选核心进行。最初，我们将使用已建立的转换的细胞系，该细胞系充当染色体不稳定性的模型系统，因为它稳定地保持了一致的拼写曲。然后，我们将确认原代人细胞中的命中。这些基因将代表治疗药物的好候选者。最后，可以通过使用Chembridge Corporation图书馆筛选恢复物，在华盛顿大学的Quellos高吞吐量筛查核心可用的115,000个小分子筛选来发现新的疗法。