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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：
8206492
负责人：
Angelique Wright Whitehurst
金额：
$ 30.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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/8206492
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 Screening procedure 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 public health relevance 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. PUBLIC HEALTH RELEVANCE: With respect to public health, these studies will identify the dependencies that are required only in tumor cells for mitotic progression. Therefore, we will uncover novel intervention points for therapy as well as new potential combinations of existing chemotherapeutics. Importantly, the genes we are evaluating here were identified from a genome-wide analysis to identify those components with the most significant impact on tumor cell mitosis. Thus, these studies will identify the sensitive pressure points in tumor for anti-cancer therapy. Ultimately, an understanding of how these proteins support mitosis will open new avenues for therapeutic intervention

描述（由申请人提供）：癌细胞采用复杂和多样的分子机制来克服通常防止失控增殖的先天屏障[1]。为了直接解决这一复杂性，我们率先应用全基因组siRNA筛选来鉴定那些基因产物，其缺失对非小细胞肺癌细胞（NSCLC）中的紫杉醇敏感性具有最显著的影响。这项工作发现了一系列不同的候选人，其中许多人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个新的和功能多样的基因，其在有丝分裂中的作用还没有以前的特点。由于这些基因中的许多在肿瘤中显示出升高的表达模式，我们假设它们可能是细胞周期进展的肿瘤细胞特异性依赖性。该建议的目的是这些基因的功能的机制阐述，就其对体内有丝分裂和肿瘤生长的影响而言。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，了解这些蛋白质如何支持有丝分裂将为治疗干预开辟新的途径。公共卫生关系：在公共卫生方面，这些研究将确定只有肿瘤细胞才需要有丝分裂进展的依赖性。因此，我们将发现新的治疗干预点以及现有化疗药物的新的潜在组合。重要的是，我们在这里评估的基因是从全基因组分析中鉴定出来的，以鉴定对肿瘤细胞有丝分裂影响最显著的那些成分。因此，这些研究将确定肿瘤的敏感压力点，用于抗癌治疗。最终，了解这些蛋白质如何支持有丝分裂将为治疗干预开辟新的途径