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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：
8688658
负责人：
Linda Wordeman
金额：
$ 20.16万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688658
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 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 public health relevance screening small molecule 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(申请人提供)：染色体不稳定导致癌症达到非整倍体的状态，而非整倍体又被认为是导致肿瘤发生的突变的驱动因素。这个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。具体地说，我们有初步数据表明，微管聚合率的增加与染色体不稳定性有关，微管聚合率是微管动态调节变化的读数。此外，根据已建立的信号通路，导致微管动力学增加的损害并不总是可预测的。我们已经开发了一种相对简单的目测方法，用于检测导致微管聚合率增加的病变。我们还发现，微管聚合速率可以通过调节分子的实验改变来挽救和恢复到正常水平，其中一些已知可以通过小分子抑制剂来管理。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，这些改变可能优先对某些治疗类别产生反应。我们的方法是筛选那些丢失导致微管聚合率增加的基因。这些筛选将在华盛顿大学的Quellos High Throughout Screen Core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。然后我们将确认在原代人类细胞中有命中。这些基因将是治疗药物的良好候选者。最后，可以通过使用位于华盛顿大学干细胞和再生医学研究所的Quellos High Throughput Screen Core的ChemBridge公司包含115,000个小分子的库来筛选回复变种，从而发现新的治疗方法。