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Mechanistic Elaboration of Fragility in the Cancer Cell Mitotic Spindle

癌细胞有丝分裂纺锤体脆性的机制阐述

基本信息

批准号：
8720972
负责人：
Angelique Wright Whitehurst
金额：
$ 26.79万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-13 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720972
关键词：
Address Adult Algorithms Binding Proteins Cell Cycle Progression Cessation of life Collection Complex Data Set Defect Dependency Development Dose Follow-Up Studies Gametogenesis Gene Expression Gene Mutation Genes Genetic Genome Goals Intervention KRAS2 gene Lung Adenoma Lung Neoplasms Malignant Neoplasms Microtubules Mitosis Mitotic Mitotic Spindle Apparatus Mitotic spindle Mitotic/Spindle Checkpoint Molecular Non-Small-Cell Lung Carcinoma Normal Cell Nuclear Oncogenes Paclitaxel Pattern Phenocopy Play Polyadenylation Predisposition Process Production Proteins Public Health Research Role Runaway Scaffolding Protein Small Interfering RNA Solid Neoplasm TACC3 gene Testicular Neoplasms Testing Therapeutic Intervention Tissues Triage Tubulin Tumor Antigens Validation Work acrosin biological systems cancer cell cancer testis antigen cancer therapy cohort daughter cell fitness gene function genome-wide genome-wide analysis in vivo member neoplastic cell novel novel therapeutic intervention ovarian neoplasm pressure prevent programs screening tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Cancer cells employ complex and multifarious molecular mechanisms to overcome innate barriers that normally prevent runaway proliferation[1]. To address this complexity directly, we have pioneered the application of genome-wide siRNA screening to identify those gene products whose depletion has the most significant impact on paclitaxel sensitivity in Non-Small Cell Lung Cancer cells (NSCLC). This effort uncovered a collection of diverse candidates many of whom appear to be the products of anomalous gene expression programs and only impact mitosis in tumor cells. Using a stringent objective statistical algorithm and experimental validation, we have identified 3 novel and functionally diverse genes, whose role in mitosis has not previously been characterized. Because many of these genes display elevated expression patterns in tumors, we hypothesize that they may be tumor-cell specific dependencies for cell cycle progression. The purpose of this proposal is the mechanistic elaboration of the function of these genes with respect to their impact on mitosis and tumor growth in vivo. The long-term objective of this work is to deconstruct the components that are uniquely required for tumor cell mitosis. Ultimately, an understanding of how these proteins support mitosis will open new avenues for therapeutic intervention.

描述(由申请人提供)：癌细胞使用复杂和多样的分子机制来克服通常防止失控扩散的先天障碍[1]。为了直接解决这种复杂性，我们率先应用全基因组siRNA筛选来确定其缺失对非小细胞肺癌细胞(NSCLC)紫杉醇敏感性有最显著影响的基因产物。这项工作发现了一系列不同的候选基因，其中许多似乎是异常基因表达程序的产物，只影响肿瘤细胞的有丝分裂。使用严格的客观统计算法和实验验证，我们已经确定了3个新的和功能不同的基因，它们在有丝分裂中的作用以前没有被描述过。因为这些基因中的许多在肿瘤中表现出高表达模式，我们假设它们可能是肿瘤细胞对细胞周期进程的特异性依赖。这一建议的目的是机械地阐述这些基因在体内对有丝分裂和肿瘤生长的影响方面的功能。这项工作的长期目标是解构肿瘤细胞有丝分裂所需的独特成分。最终，对这些蛋白质如何支持有丝分裂的了解将为治疗干预开辟新的途径。