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）：本提案是一项竞争性修订申请，以授予 5 R01 GM082834-02“胞质分裂的小分子探针”，以响应通知号 NOT-OD-09-058“NIH 宣布恢复法案的可用性”竞争性修订申请资金”。细胞如何调节和执行胞质分裂（细胞分裂的最后一步）仍然是基础生物学中未解决的主要问题。我们的长期目标是系统地剖析胞质分裂过程中的时间和空间控制。用传统方法研究胞质分裂一直具有挑战性，因为它是一个快速过程，并且许多关键的胞质分裂蛋白也在细胞周期的早期发挥重要功能。小分子作用迅速且具有高度时间控制能力，是研究胞质分裂的理想工具。我们发现了几种新型的胞质分裂小分子抑制剂，母基金的重点是了解其中三种化合物的机制。为了增加小分子工具库，我们建议发现针对胞质分裂调节途径（特别是 Rho 途径）的分子。我们将使用 RNAi 来创建敏化细胞，使我们能够检测特定的抑制剂并通过类似于上位分析的简单方法识别小分子靶标。我们设计了一种跨学科方法，结合化学、成像技术和生物化学，利用我们的小分子来探究 Rho 途径在胞质分裂中的作用。该提案将新技术方法的开发与同时应用于基本且重要的生物学问题结合起来。 公共卫生相关性：细胞分裂（细胞分裂的最后一步）背后的许多机制仍然知之甚少。细胞分裂失败是癌症等疾病的原因或促成因素。专门针对胞质分裂，特别是 Rho 信号通路的小分子，是研究细胞分裂的基础生物学的重要工具，并且可以催化治疗癌症的治疗药物的发现。