Mechanisms of centriole assembly and stability

中心粒组装和稳定性机制

• 批准号: 9119844
• 负责人: CHAD G PEARSON
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119844
• 关键词: Address; Architecture; Biochemical; Blindness; Cells; Centrioles; Centrosome; Child; Chromosome Segregation; Cilia; Collaborations; Complex; Computer Simulation; Congenital Abnormality; Core Protein; Defect; Dependency; Etiology; Event; Extracellular Fluid; Figs - dietary; Goals; Human; Image Analysis; In Vitro; Level of Evidence; Life; Link; Location; Maintenance; Malignant Neoplasms; Mature Centriole; Mechanics; Mental Retardation; Microtubule Triplet; Microtubules; Molecular; Molecular Genetics; Movement; Obesity; Pathology; Polycystic Kidney Diseases; Population; Positioning Attribute; Process; Proteins; Proteomics; Recruitment Activity; Research; Research Assistant; Research Personnel; Resistance; Role; Shapes; Signal Transduction; Structural defect; Structure; Tertiary Protein Structure; Testing; Tetrahymena; Time; Training; Tubulin; base; ciliopathy; cilium biogenesis; experience; graduate student; human disease; link protein; member; molecular assembly/self assembly; nanomachine; novel; protein complex; protein function; quantitative imaging; reconstitution; respiratory; scaffold; undergraduate student

DESCRIPTION (provided by applicant): Centrioles are cellular nanomachines that nucleate and organize centrosomes and cilia. Defects in centrioles contribute to both cancer and ciliopathies. Ciliopathies are a general class of human maladies that include child birth defects, mental retardation, polydactyl, blindness, obesity, and polycystic kidneys. However, the mechanics of centriole formation that, when defective, contribute to the above pathologies are not well understood. Our long term goals are to understand the etiology of such defects. Toward this goal, we will study two important events in centriole formation and function; assembly and stabilization. Both of these events are vital for centrosomes and cilia. An essential centriole structure that is required for both of these events is the cartwheel. To elucidate the molecular assembly of a cartwheel, biochemical, molecular-genetic, and quantitative imaging tactics will be employed. First, we will determine how a novel complex of cartwheel components stabilizes centrioles. Second, we will define how and when protein components interact to build the cartwheel and centriole architecture. Third, one member of the stability complex is Bld10/Cep135 that, in addition to its stability role, is essential for centriole assembly. Bld10's roles in centriole function will be determined by separating its functions in centriole assembly and maintenance and identifying the proteins it interacts with to perform these functions. We will establish the key proteins and the mechanisms for cartwheel and centriole assembly into a stable structure. Building on this stable structure, we can then define how this platform nucleates cilia and centrosomes. This proposal will develop our long term goals to reconstitute cartwheel and centriole assembly and to understand how defects in these processes cause human disease. Our studies will be carried out by a collaborative group of researchers. These studies will provide excellent training experiences for undergraduate and graduate students and postdoctoral researchers and professional research assistants. Collaborations with other labs that include computational modeling, quantitative image analysis, and proteomics will expand the impact of our studies.

描述（由申请人提供）：中心粒是细胞纳米机器，形成中心体和纤毛。中心粒缺陷导致癌症和纤毛病。纤毛病是一类常见的人类疾病，包括儿童出生缺陷、智力迟钝、多趾畸形、失明、肥胖和多囊肾。然而，中心粒形成的机制，当缺陷时，有助于上述病理尚不清楚。我们的长期目标是了解这些缺陷的病因。为了实现这一目标，我们将研究中心粒形成和功能中的两个重要事件；装配和稳定。这两个过程对中心体和纤毛都是至关重要的。这两种运动都需要一个重要的中心粒结构，那就是侧翻。为了阐明侧手翻的分子组装，生化、分子遗传学和定量成像策略将被采用。首先，我们将确定一个新的车轮成分复合物是如何稳定中心粒的。其次，我们将定义蛋白质成分如何以及何时相互作用以构建侧轮和中心粒结构。第三，稳定复合物的一个成员是Bld10/Cep135，除了其稳定作用外，它对中心粒组装至关重要。Bld10在中心粒功能中的作用将通过分离其在中心粒组装和维持中的功能以及识别与之相互作用以执行这些功能的蛋白质来确定。我们将建立关键蛋白质和机制的车轮和中心粒组装成一个稳定的结构。在这个稳定结构的基础上，我们可以确定这个平台是如何形成纤毛和中心体的。这一建议将发展我们的长期目标，以重建侧轮和中心粒组装，并了解这些过程中的缺陷如何导致人类疾病。我们的研究将由一个研究人员合作小组进行。这些研究将为本科生和研究生以及博士后研究人员和专业研究助理提供良好的培训经验。与其他实验室的合作，包括计算建模、定量图像分析和蛋白质组学，将扩大我们研究的影响。