Centriole assembly and function for centrosome and cilia biology

中心体和纤毛生物学的中心粒组装和功能

• 批准号: 10580087
• 负责人: CHAD G PEARSON
• 金额: $ 56.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580087
• 关键词: Affect; Back; Biology; Cardiac; Cell Cycle; Cell Mobility; Cells; Cellular Morphology; Centrioles; Centrosome; Cilia; Cytoplasm; Development; Disease; Down Syndrome; Event; Foundations; Future; Genes; Genome; Goals; Homeostasis; Immune; Individual; Malignant Neoplasms; Mechanics; Messenger RNA; Metabolism; Microtubules; Mitosis; Mitotic spindle; Molecular Structure; Normal Cell; Process; Proteins; RNA metabolism; Reproduction; Research; Resistance; Role; S phase; Secretory Cell; Sensory; Signal Transduction; Spatial Distribution; System; Testing; Tissues; Vision; cancer cell; cell cortex; cell type; cilium motility; dosage; extracellular; fluid flow; hydrodynamic flow; mechanical force; novel; programs; respiratory; scaffold; segregation; targeted treatment; trafficking; transmission process

PROJECT SUMMARY/ABSTRACT Overview. Centrioles, and the centrosomes they scaffold, organize the cell, and provide the foundation for development and tissue homeostasis. To do this, centrioles exert control over the cell's microtubule (MT) network, providing a micron-scale framework for intracellular trafficking, intracellular and extracellular signaling, genome segregation, cell morphology, and cell mobility. To perform these roles, centrioles change through the cell cycle via the processes of new centriole assembly and modulations to scaffolding functions. During a normal cell cycle, centrioles nucleate the sensory and signaling compartment of cilia in G0/G1, duplicate coincident with the genome during S-phase, and organize the mitotic spindle during mitosis. In cancer and Trisomy 21 (the cause of Down syndrome), these mechanisms are disrupted. In specialized multiciliated cell types, centrioles nucleate motile cilia which generate fluid flows necessary for reproduction, development, and respiratory airway function. How centrioles are controlled, function and resist mechanical forces remain poorly understood. Goals for five years. We aim to dissect poorly understood mechanisms in how centrioles duplicate, how MT- based intracellular trafficking and cilia are controlled by centrosome protein dosage, and how centrioles provide the foundation for mechanical forces from motile cilia. We will investigate novel controls of centriole duplication either through spatial distributions of regulatory factors or through mRNA metabolism that generates functionally different proteins from the same gene. We will determine how imbalances in centriole number and centriole protein dosage, as observed in cancer and Trisomy 21, impact cytoplasmic MTs and intracellular trafficking for primary cilia formation and signaling. Finally, we will illuminate how centrioles act as force capacitors for motile cilia through connections to neighboring centrioles and the cell cortex and ask if they transmit forces back to cilia. These projects will establish the fundamental mechanics of centrioles as they assemble primary cilia for signaling and motile cilia for hydrodynamic flow. Vision for program. Discoveries in the fundamentals of centriole and centrosome biology, focusing on MT- dependent trafficking and mechanical force resistance, will have broad implications for understanding aspects of development, mechanobiology, and disease. Changes in RNA metabolism have a critical role in development, and by establishing mRNA processing events that affect centrioles and the MT network we anticipate identifying targets important for specialized cell types that utilize their MT networks in very different ways. Furthermore, our current studies in Trisomy 21 are pointing toward exciting future directions for understanding the cellular basis of cardiac, immune, and secretory cell systems directly impacted in Down syndrome.

项目总结/摘要 概况.中心粒和它们所支撑的中心体组织细胞，并为细胞的生长提供基础。 发育和组织稳态。为了做到这一点，中心粒发挥控制细胞的微管（MT） 网络，为细胞内运输，细胞内和细胞外信号传导， 基因组分离、细胞形态和细胞移动性。为了发挥这些作用，中心粒通过 通过新的中心粒组装和对支架功能的调节来调节细胞周期。期间 正常细胞周期，中心粒在G 0/G1期使纤毛的感觉和信号室成核，重复 在S期与基因组一致，并在有丝分裂期间组织有丝分裂纺锤体。在癌症和 三体21（唐氏综合症的原因），这些机制被破坏。在特化的多纤毛细胞中 型，中心粒成核运动纤毛，产生生殖，发育所需的流体流动， 呼吸道功能中心粒是如何被控制、发挥作用和抵抗机械力的， 明白 五年的目标。我们的目标是剖析中心粒如何复制，MT如何复制， 基于细胞内运输和纤毛控制的中心体蛋白剂量，以及中心粒如何 为来自运动纤毛的机械力提供基础。我们将研究中心粒的新控制 通过调节因子的空间分布或通过mRNA代谢复制， 从同一基因中产生功能不同的蛋白质。我们将确定中心粒的不平衡 如在癌症和21三体中观察到的，数量和中心粒蛋白剂量影响细胞质MT， 用于初级纤毛形成和信号传导的细胞内运输。最后，我们将阐明中心粒如何作为 通过与邻近中心粒和细胞皮层的连接，迫使运动纤毛的电容器，并询问它们是否 将力传递回纤毛这些项目将建立中心粒的基本力学， 组装初级纤毛用于信号传递，组装运动纤毛用于流体动力学流动。 方案愿景。中心粒和中心体生物学基础的发现，重点是MT- 依赖贩运和机械力阻力，将有广泛的影响，了解方面 发展，机械生物学，和疾病。RNA代谢的变化在 通过建立影响中心粒和MT网络的mRNA加工事件， 预期识别对专门细胞类型重要的目标，这些细胞类型以非常不同的方式利用它们的MT网络。 的方式此外，我们目前对21三体的研究指向了令人兴奋的未来方向， 了解心脏，免疫和分泌细胞系统的细胞基础直接影响在唐 综合征