Centrosome Structure, Function and Duplication

中心体结构、功能和复制

• 批准号: 8696153
• 负责人: Tim Stearns
• 金额: $ 45.5万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696153
• 关键词: Address; Adult; Animals; Binding; Biological Assay; Brain; Cell Cycle; Cell division; Cells; Cellular Structures; Cellular biology; Centrioles; Centrosome; Chromosomes; Cilia; Complex; Core Protein; DNA; DNA Repair; DNA biosynthesis; Defect; Development; Disease; Drosophila genus; Failure; Fiber; Genome; Human; In Situ; Knowledge; Link; Malignant Neoplasms; Mammalian Cell; Microcephaly; Microtubules; Mitotic spindle; Molecular; Mothers; Neurons; Normal Cell; Nuclear; Organelles; Organism; Pathway interactions; Phenotype; Process; Protein Kinase; Proteins; Reagent; Recruitment Activity; Regulation; Regulatory Pathway; Replication Origin; Research; Role; Signal Transduction; Site; Spottings; Structural Protein; Structure; System; Technology; Testing; Tissue Extracts; Vertebrates; Work; ciliopathy; developmental disease; interest; neuron development; overexpression; public health relevance; research study

DESCRIPTION (provided by applicant): The central problems addressed in the proposed research are how the centrosome is organized, how it duplicates once per cell cycle, and how we go from the "parts list" for the organelle to a more complete understanding of how it works. The centrosome nucleates microtubules and helps to organize those microtubules to create useful arrays, including the mitotic spindle and the cilium. Work from my lab and others over the last 20 years at Stanford has identified molecules involved in microtubule nucleation, the central regulators of centrosome duplication, important structural proteins involved in duplication, and control mechanisms that govern centrosome number and link the centrosome and the cilium. Interest in the centrosome is strong because of the correlation between centrosome abnormalities and the development of cancer, and because of the role of the centrosome in ciliopathies, diseases related to primary cilium function, and microcephaly, a defect in neuronal development. The proposed experiments make use of the strengths that we have developed in reagents and assays for studying centrosome structure, function and duplication in different experimental systems. We have chosen to focus on the process in animal cells, tissues and extracts as they are the systems most relevant to our desire to understand the human centrosome in normal cell division, and in disease. Three specific aims are addressed in this proposal: Specific Aim 1 - Identify and characterize the interactions that define the centriole "origin of duplication" Specific Aim 2 - Characterize the mode of action of Mdm1, a unique negative regulator of centriole duplication. Specific Aim 3 - Create centriole-less mammalian cells to address the function of the centrosome in the cell cycle, cell signaling, and nuclear functions.

描述（由申请人提供）：在拟议的研究中解决的中心问题是中心体是如何组织的，它如何在每个细胞周期复制一次，以及我们如何从细胞器的“部件列表”更完整地了解它是如何工作的。中心体使微管成核，并帮助组织这些微管以产生有用的阵列，包括有丝分裂纺锤体和纤毛。过去20年来，我的实验室和其他人在斯坦福大学的工作已经确定了参与微管成核的分子，中心体复制的中心调节因子，参与复制的重要结构蛋白，以及控制中心体数量和连接中心体和纤毛的控制机制。由于中心体异常与癌症发展之间的相关性，以及中心体在纤毛病（与初级纤毛功能相关的疾病）和小头畸形（神经元发育缺陷）中的作用，因此对中心体的兴趣很强。所提出的实验利用了我们在不同实验系统中研究中心体结构、功能和复制的试剂和测定中开发的优势。我们选择专注于动物细胞，组织和提取物中的过程，因为它们是与我们理解正常细胞分裂和疾病中人类中心体的愿望最相关的系统。本提案提出了三个具体目标：具体目标1 -确定和表征定义中心粒“复制起源”的相互作用具体目标2 -表征Mdm 1的作用模式，Mdm 1是中心粒复制的独特负调节因子。具体目标3 -创建无中心粒的哺乳动物细胞，以解决中心体在细胞周期，细胞信号传导和核功能中的功能。