Cell and Chemical Biology of Microtubules

微管的细胞和化学生物学

• 批准号: 10642769
• 负责人: Timothy J Mitchison
• 金额: $ 83.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642769
• 关键词: Adult; Axon; Binding Sites; Biochemistry; Biological Models; Biology; Cell Culture Techniques; Cell division; Cell surface; Cells; Cellular biology; Chemicals; Chromosomes; Colchicine; Communication; Congenital Abnormality; Cytoplasm; Disease; Distant; Dose; Drug Targeting; Gout; Human; Human body; Infertility; Inflammatory; Knowledge; Learning; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Medicine; Microscopy; Microtubules; Mitotic spindle; Molecular; Motor Neuron Disease; Myocardial Infarction; Neurons; Paclitaxel; Pharmaceutical Preparations; Polymers; Positioning Attribute; Proteins; Rana; Research; Rodent Model; Synapses; Testing; Therapeutic; Tubulin; Work; cancer therapy; drug action; egg; human disease; human tissue; improved; insight; malignant breast neoplasm; mathematical model; prevent; stathmin; tool

Project Summary/Abstract: We will investigate the cell and chemical biology of microtubules in order to answer fundamental questions of cell organization and improve treatment of human diseases. Microtubules are dynamic, linear polymers of the protein tubulin. They physically organize the cytoplasm of most human cells, and serve as transport tracks for moving cellular components. They are particularly important during cell division, when they build mitotic spindles which separate chromosomes, and in neurons, where they provide transport tracks for supplying distant synapses with new building blocks. We will probe cell division mechanism using frog eggs as a model system. Our work may help treat infertility and understand mistakes in cell division that give rise to birth defects. We k now most of the proteins required for cell division, but we do not know how they work together to build spindles or position cleavage furrows. We will use a new tool, quantitative mass spectrometry, to simultaneously measure hundreds of proteins in mitotic spindles in frog egg extracts, and how they compete for binding sites on microtubules. We will also combine microscopy, biochemistry and mathematical modeling to learn how the spindle communicates with the cell surface to position cleavage furrows. In neurons, we will investigate how tubulin is transported down axons, and test a new hypothesis in which stathmin proteins serve as transport adapters. This work will address a fundamental question in neuronal cell biology, and may help treat motor neuron disease (ALS). Drugs that target microtubules and are used as medicines can provide important insights into microtubule biology in adult human tissues. These include paclitaxel, which is used to treat breast and lung cancer, and colchicine, which is used to treat gout and other inflammatory diseases. We understand the molecular actions of these drugs on microtubules in detail, but not how they act in the human body to treat disease. We have developed new hypothesis for the therapeutic action of both drug classes, and will test these in cell culture and rodent models. This work could lead to new uses of old drugs, for example we suspect low doses of colchicine might be useful to prevent heart attacks and slow the progression of lung cancer. It could also lead to replacement drugs that are more active and less toxic. PHS 398/2590 (Rev. 11/07) Continuation Format Page

项目摘要/摘要： 我们将研究微管的细胞和化学生物学，以回答基本问题 细胞组织问题并改善人类疾病的治疗。微管是 蛋白质微管蛋白的动态线性聚合物。它们以物理方式组织大多数细胞的细胞质 人类细胞，并充当移动细胞成分的运输轨道。他们特别 在细胞分裂过程中很重要，当它们形成分离染色体的有丝分裂纺锤体时， 在神经元中，它们提供传输轨道，为远处的突触提供新的构建 块。我们将使用青蛙卵作为模型系统来探讨细胞分裂机制。我们的工作可能 帮助治疗不孕症并了解导致出生缺陷的细胞分裂错误。我们现在知道了 细胞分裂所需的大部分蛋白质，但我们不知道它们如何共同构建 纺锤体或位置解理沟。我们将使用一种新工具，定量质谱法， 同时测量青蛙卵提取物中有丝分裂纺锤体中的数百种蛋白质，以及它们如何 竞争微管上的结合位点。我们还将结合显微镜、生物化学和 数学建模以了解主轴如何与细胞表面通信以进行定位 解理沟。在神经元中，我们将研究微管蛋白如何沿着轴突运输，并测试 Stathmin 蛋白作为转运接头的新假设。这项工作将解决一个 神经细胞生物学的基本问题，可能有助于治疗运动神经元疾病（ALS）。 针对微管并用作药物的药物可以提供重要的见解 成人组织中的微管生物学。其中包括用于治疗乳腺癌的紫杉醇 和肺癌，以及用于治疗痛风和其他炎症性疾病的秋水仙碱。我们 详细了解这些药物对微管的分子作用，但不了解它们在微管中的作用方式 从而达到治疗人体疾病的目的。我们针对其治疗作用提出了新的假设 两种药物类别，并将在细胞培养和啮齿动物模型中测试这些药物。这项工作可能会导致 旧药的新用途，例如，我们怀疑低剂量的秋水仙碱可能有助于预防 心脏病发作并减缓肺癌的进展。它还可能导致替代药物 更活跃且毒性更小。 PHS 398/2590（修订版 11/07）继续格式页