Centriole assembly and function for centrosome and cilia biology

项目摘要/摘要 概述。中心粒和它们构成的中心体，组织细胞，并为 发育和组织动态平衡。为此，中心粒对细胞的微管(MT)施加控制 网络，为细胞内运输、细胞内和细胞外信号传递提供微米级框架， 基因组分离、细胞形态和细胞迁移率。为了扮演这些角色，中心粒通过 通过新的中心粒组装和对支架功能的调制来实现细胞周期。在一次 正常的细胞周期，中心粒使G0/G1中纤毛的感觉和信号间隔成核，重复 在S期与基因组重合，在有丝分裂时组织有丝分裂纺锤体。在癌症和 21三体(唐氏综合症的原因)，这些机制被打乱。在专门的多纤毛细胞中 类型，中心粒成核的活动纤毛，产生繁殖，发育和 呼吸道功能。中心粒的控制、作用和抵抗机械力的方式仍然很差。 明白了。 五年的目标。我们的目标是剖析鲜为人知的中心粒如何复制、MT如何复制的机制。 基于细胞内的转运和纤毛由中心体蛋白的剂量和中心粒如何控制 从可移动的纤毛中提供机械力的基础。我们将研究中心粒的新控制 复制要么通过调节因子的空间分布，要么通过 从同一基因产生不同功能的蛋白质。我们将确定中心粒的不平衡是如何 数量和中心粒蛋白剂量，如在癌症和21三体中观察到的，影响细胞质MTS和 初级纤毛形成和信号的细胞内运输。最后，我们将说明中心粒如何作为 通过连接到邻近的中心粒和细胞皮质来迫使电容器运动纤毛，并询问它们是否 把力量传回纤毛。这些项目将建立中心粒的基本机制，因为它们 组装初级纤毛用于信号传递，并组装活动纤毛用于流体动力流动。 节目的愿景。中心粒和中心体生物学基础方面的发现，重点是MT- 依赖贩运和机械阻力，将对理解方面产生广泛的影响 发育、机械生物学和疾病。RNA新陈代谢的变化在 发展，并通过建立影响中心粒和MT网络的mRNA处理事件，我们 预计识别对在非常不同的情况下利用其MT网络的特定小区类型重要的目标 方式。此外，我们目前对21三体的研究指出了令人兴奋的未来方向 了解唐氏综合症直接影响心脏、免疫和分泌细胞系统的细胞学基础 综合症。

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.