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Structure and mechanism of the centrosome-cilium complex

中心体-纤毛复合物的结构和机制

基本信息

批准号：
10594530
负责人：
Tim Stearns
金额：
$ 64.85万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

项目摘要

Abstract The centrosome-cilium complex is a critical organelle of animal cell function. The centrosome is the main microtubule organizing center of animal cells, and the centrioles within the centrosome have a unique structure that allows them to serve as initiators of the assembly of a cilium. Primary cilia are small, antenna-like organelles critical for vertebrate development and physiology. Defects in the centrosome-cilium complex result in human diseases called ciliopathies, characterized by a wide spectrum of phenotypes, highlighting their important role in multiple cell types and organs. This complex forms a distinct compartment of the cell, with a highly polarized microtubule cytoskeleton directing intracellular traffic to and from it, and a specialized segment of the plasma membrane surrounding part of it. In most cells, there is only one centrosome-cilium complex, but this is often altered in cells from a range of diseases, and in cells that have specific developmental programs to amplify centrioles. The function of cilia critically depends on the dynamic changes in protein composition and localization. In particular, Hedgehog (Hh) signaling transduction, essential for embryonic development, adult tissue regeneration and cancer, largely takes place at primary cilia, and involves movements of the signaling proteins into and out of the cilium in response to signal. We have defined six fundamental questions that drive the proposed research. 1) How do the specialized compound microtubules of centriole form, and how do they specifically form only at the centriole? 2) How are centrioles functionalized to carry out the essential roles of cilium formation, centrosome formation, duplication? 3) What are the consequences of failure to maintain centriole number, and what homeostatic mechanisms exist that could facilitate a return to the normal state? 4) What mechanisms promote centriole amplification and loss in specific differentiated contexts? 5) What is the behavior of signaling proteins in the cilium, at the single molecule level, and how does it change in response to activation of the pathway? 6) How are cilia disassembled and is the same mechanism used in different contexts and across evolution? We will use a combination of advanced imaging, cell culture and in vitro differentiation models, combined with sophisticated molecular biology to address these questions. Successful outcomes in these experiments will inform our understanding of centrosome-cilium defects in disease states, including ciliopathies and cancer, and potentially lead to new therapeutic approaches. !

摘要中心体-纤毛复合体是动物细胞功能的重要细胞器。中心体是动物细胞的主要微管组织中心和中心体内的中心粒具有独特的结构，使它们能够作为纤毛组装的引发剂。初级纤毛是小的触角状细胞器，对脊椎动物的发育至关重要， physiology.中心体-纤毛复合体的缺陷导致人类疾病，纤毛病变，其特征在于广泛的表型，突出了它们在多种细胞类型和器官该复合物形成细胞的独特隔室，高度极化的微管细胞骨架，引导细胞内交通进出，围绕其一部分的质膜的专门部分。在大多数细胞中，只有一个中心体-纤毛复合体，但这在一系列疾病的细胞中经常改变，在细胞中有特定的发育程序来扩增中心粒。纤毛的功能关键取决于蛋白质组成和定位的动态变化。特别是，刺猬（Hh）信号传导，对胚胎发育、成人组织至关重要再生和癌症，主要发生在初级纤毛，并涉及运动的信号蛋白进出纤毛以响应信号。我们定义了六个推动拟议研究的基本问题。 1)中心粒的特化复合微管是如何形成的？只在中心粒形成 2)中心粒是如何功能化以执行纤毛形成的基本角色的，中心体的形成，复制？ 3)维持中心粒数量失败的后果是什么？是否存在有助于恢复正常状态的机制？ 4)在特定的分化背景下，什么机制促进中心粒的扩增和丢失？ 5)在单分子水平上，纤毛中的信号蛋白的行为是什么？它会随着通路的激活而改变吗 6)纤毛是如何分解的，在不同的情况下是否使用相同的机制，跨越进化？我们将结合先进的成像、细胞培养和体外分化模型，结合复杂的分子生物学来解决这些问题。成功这些实验的结果将有助于我们理解中心体纤毛缺陷，疾病状态，包括纤毛病变和癌症，并可能导致新的治疗接近。 !