Small molecule probes of cytokinesis

胞质分裂的小分子探针

• 批准号: 7808559
• 负责人: ULRIKE S EGGERT
• 金额: $ 35.42万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808559
• 关键词: Adhesions; Affect; Biochemistry; Biological; Biology; Cell Cycle; Cell division; Cell physiology; Cells; Chemistry; Classification; Cytokinesis; Development; Disease; Dissection; Funding; Genetic Epistasis; Goals; Grant; Imaging Techniques; Malignant Neoplasms; Methods; Pathway interactions; Pharmaceutical Preparations; Phenotype; Process; Proteins; RNA Interference; Recovery; Regulation; Regulatory Pathway; Role; Screening procedure; Signal Pathway; Therapeutic; United States National Institutes of Health; cancer type; design; enzyme activity; inhibitor/antagonist; interdisciplinary approach; migration; novel; parent grant; public health relevance; response; rho; small molecule; tool

DESCRIPTION (provided by applicant): This proposal is an application for a competitive revision to grant 5 R01 GM082834-02 "Small molecule probes of cytokinesis" in response to Notice Number NOT-OD-09-058 "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". How cells regulate and execute cytokinesis, the final step in cell division, remain major unsolved questions in basic biology. Our long-term goal is the systematic dissection of temporal and spatial control during cytokinesis. It has been challenging to study cytokinesis with traditional methods because it is a rapid process and many key cytokinesis proteins also perform important functions earlier in the cell cycle. Small molecules, which act rapidly and with high temporal control, are ideal tools to study cytokinesis. We discovered several novel small molecule inhibitors of cytokinesis, and the parent grant focuses on understanding the mechanism of three of these compounds. To increase the pool of small molecule tools, here we propose to discover molecules that target regulatory pathways in cytokinesis, specifically the Rho pathway. We will use RNAi to create sensitized cells that will allow us to detect specific inhibitors and identify small molecule targets by a straightforward approach similar to epistasis analysis. We have designed an interdisciplinary approach, combining chemistry, imaging techniques and biochemistry to use our small molecules to probe the role of the Rho pathway in cytokinesis. This proposal combines the development of new technological approaches with simultaneous application to a fundamental and important biological question. PUBLIC HEALTH RELEVANCE: Many mechanisms underlying cytokinesis, the final step in cell division, remain poorly understood. Failed cell division is causal or contributory in diseases such as cancer. Small molecules that specifically target cytokinesis and in particular the Rho signaling pathway, are important tools to study the underlying biology of cell division and could catalyze the discovery of therapeutic drugs to treat cancer.

描述（由申请人提供）：该提案是对竞争性修订的申请，以授予5 R01 GM082834-02“小分子细胞因子探针”，以响应通知号，而不是OD-OD-09-058” NIH宣布恢复ACT ACT资金的可用性用于有竞争性的修订应用程序。细胞如何调节和执行细胞因子（细胞分裂的最后一步）仍然是基本生物学中的主要尚未解决的问题。我们的长期目标是细胞因子期间时间和空间控制的系统解剖。使用传统方法研究细胞因子是一个挑战，因为这是一个快速过程，许多关键的细胞因子蛋白在细胞周期早期也执行重要功能。小分子迅速起作用并具有高时间控制，是研究细胞因子的理想工具。我们发现了几种新型细胞因子的小分子抑制剂，父母的授予专注于理解这些化合物中的三种机制。为了增加小分子工具的池，我们在这里提议发现靶向细胞因子（特别是RHO途径）的分子。我们将使用RNAi创建敏化细胞，使我们能够通过类似于上科学分析的直接方法来检测特定的抑制剂并识别小分子靶标。我们设计了一种跨学科方法，结合了化学，成像技术和生物化学，以使用我们的小分子来探测Rho途径在细胞因子中的作用。该建议将新技术方法的发展与同时应用于基本和重要的生物学问题的同时应用。 公共卫生相关性：细胞因子的基本机制，即细胞分裂的最后一步，仍然对知识不足。失败的细胞分裂是癌症等疾病的因果关系。专门针对细胞因子，尤其是RHO信号通路的小分子是研究细胞分裂的潜在生物学的重要工具，并可能催化发现治疗癌症的治疗药物。