Molecular Analysis of the Kinetochore-Microtubule Interface

着丝粒-微管界面的分子分析

• 批准号: 8299046
• 负责人: Iain McPherson Cheeseman
• 金额: $ 36.31万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299046
• 关键词: Affect; Affinity; Aneuploidy; Binding; Biochemical; Biological Assay; Cause of Death; Cell Death; Cells; Chemotherapy-Oncologic Procedure; Chromosome Segregation; Chromosomes; Clinical Trials; Complex; Couples; DNA; Defect; Diagnosis; Disease; Dose-Limiting; Ensure; Foundations; Genes; Genetic; Goals; Health; Human; Human body; In Vitro; Individual; Instruction; Kinetochores; Mediating; Microtubule Depolymerization; Microtubules; Mitosis; Mitotic; Modeling; Molecular; Molecular Analysis; Movement; Mutation; Nature; Nervous system structure; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Polymers; Process; Property; Protein Binding; Proteins; Regulation; Role; Sister Chromatid; Site; Structure; Testing; Work; aurora B kinase; base; cancer cell; cancer therapy; chemotherapy; chromosome movement; daughter cell; fungus; in vivo; inhibitor/antagonist; neurotoxicity; protein structure; research study; retinal rods; segregation; small molecule; tumor; tumor progression; tumorigenesis; upstream kinase

DESCRIPTION (provided by applicant): Each cell in the human body contains 46 different chromosomes, large units of DNA that encode instructions for that cell to grow, divide, and carry out its specialized functions. During mitosis, when a cell divides, each of these chromosomes must be accurately distributed to the two new daughter cells. If this process occurs incorrectly for even a single chromosome, the resulting daughter cells will lose or gain thousands of genes and the instructions that they contain. This type of error in chromosome segregation can result in the death of the cell and is thought to contribute to tumorigenesis. Indeed, as many as 70% of tumors are observed to have abnormal numbers of chromosomes. To facilitate the segregation of DNA during mitosis, chromosomes must generate physical attachments to rod-like polymers termed microtubules that provide the structure and forces to move the chromosomes. Anti-mitotic drugs that disrupt the ability of these microtubules to connect with the chromosomes are routinely used for cancer chemotherapy. However, many of these drugs have deleterious secondary affects due to additional roles for microtubules in the nervous system. A key player in chromosome segregation is a large proteinaceous structure termed the kinetochore that forms the interface between the chromosomes and the microtubules. Inhibition of kinetochore activities is predicted target cancer cells while avoiding the dose-limiting neuronal toxicity associated with microtubule-binding chemotherapy drugs. Indeed, inhibitors against several kinetochore proteins are currently in clinical trials. Determining the specific activities of each human kinetochore protein is crucial to provide a context for their functions in chromosome segregation, to evaluate the best targets for the diagnosis and treatment of disease, and to generate assays suitable for the isolation of small molecule inhibitors. The proposed work will analyze the function and regulation of the human kinetochore proteins that are required to generate interactions with microtubules. This work will focus on two key, recently identified groups of kinetochore-associated proteins that bind to microtubule polymers directly. These studies will define the properties of these proteins and determine the mechanisms by which these proteins interact with microtubules, dissect their regulation by upstream kinases that control kinetochore-microtubule attachments, and examine their functions in human cells. In total, these studies will define the basis for kinetochore-microtubule interactions that will ultimately provide the foundation for experiments on the diagnosis and treatment of cancer. PUBLIC HEALTH RELEVANCE: Project Narrative Defects in mitosis that result in errors in chromosome numbers can cause the death of a cell and are thought to contribute to tumor progression. Understanding the means by which these units of DNA, and the genetic information that they contain, are evenly distributed to new cells is critical for the diagnosis and treatment of cancer. This proposed work will determine the mechanisms that direct and control chromosome segregation in human cells.

描述（由申请人提供）：人体中的每个细胞都包含46个不同的染色体，大的DNA单位，这些单位编码指令，以使该细胞生长，分裂和执行其专门功能。在有丝分裂期间，当细胞分裂时，这些染色体中的每一个都必须准确地分布在两个新的子细胞上。如果此过程甚至对于一个单个染色体也不正确地发生，则由此产生的子细胞会损失或获得数千个基因及其所包含的指令。这种类型的染色体分离误差可能导致细胞死亡，并被认为会导致肿瘤发生。实际上，观察到多达70％的肿瘤具有异常的染色体。为了促进有丝分裂过程中DNA的分离，染色体必须产生物理附着在称为微管的棒状聚合物上，这些微管提供了可移动染色体的结构和力。破坏这些微管与染色体连接能力的抗溶毒药物通常用于癌症化学疗法。但是，由于微管在神经系统中的其他作用，这些药物中的许多药物都具有有害的次要影响。染色体隔离的关键参与者是一种称为动力学的大蛋白质结构，该结构形成了染色体和微管之间的界面。动力学活性的抑制是预测的靶癌细胞，同时避免了与微管结合化疗药物相关的限制剂量的神经元毒性。实际上，目前正在临床试验中，针对几种动力学蛋白的抑制剂。确定每种人动物学蛋白的特定活性对于为其在染色体分离中的功能提供背景至关重要，以评估诊断和治疗疾病的最佳靶标，并产生适合分离小分子抑制剂的测定。拟议的工作将分析与微管相互作用所需的人类动物学蛋白的功能和调节。这项工作将集中于直接与微管聚合物结合的两个关键的，最近确定的动力学相关蛋白。这些研究将定义这些蛋白质的特性，并确定这些蛋白质与微管相互作用的机制，通过控制动物学微动物附着的上游激酶进行调节，并检查其在人类细胞中的功能。总的来说，这些研究将定义动力学微管相互作用的基础，这些相互作用最终将为诊断和治疗癌症的实验提供基础。公共卫生相关性：有丝分裂的项目叙事缺陷导致染色体数量错误可能导致细胞死亡，并被认为会导致肿瘤进展。了解这些DNA单位及其包含的遗传信息的手段均匀分布到新细胞中对于癌症的诊断和治疗至关重要。这项提出的工作将确定指导和控制人类细胞中染色体分离的机制。