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The Role of Membrane Architecture in Primary Cilium Signaling

膜结构在初级纤毛信号传导中的作用

基本信息

批准号：
10394131
负责人：
Alexandra Fitzgerald Long
金额：
$ 6.76万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2024-04-04
项目状态：
已结题

项目摘要

Project Summary Cilia are ubiquitous and important microtubule-based organelles involved in sensation, developmental signaling, fluid flow and cell motility whose dysregulation leads to a range of human disease states including cancers and ciliopathies. The non-motile primary cilium functions as a signaling antenna. It has a distinct and tightly regulated protein and lipid composition while remaining contiguous with the plasma membrane of the cell. Proper cilium function depends on compartmentalization both for spatial separation of ciliary activities and high concentration of signaling components. While there has been extensive characterization of the proteins and lipids that compose the cilium, ciliary membrane, and the diffusion barrier at its base, much less is known about the composition and function of membrane regions proximal to the cilium that support proper signaling. In many cell types, the mature primary cilium sits in a microns-deep membrane invagination called the “ciliary pocket” that is an important but under-characterized hub of endocytic activity and signaling. The ultrastructure of the ciliary pocket is highly conserved and is distinct from both the ciliary and plasma membranes. It has been difficult to clearly define the ciliary pocket as a distinct compartment and determine its full contributions to ciliary signaling and function. This is in part due to the technical challenge of imaging this diffraction limited region and lack of tools to specifically perturb the pocket’s structure and composition. In this proposal I will address this gap through an interconnected set of aims, leveraging innovative technologies including proximity-based labeling and super-resolution microscopy as well as functional signaling assays to: 1) define the molecular composition of the ciliary pocket, 2) determine how ciliary pocket structure is established and maintained to support signaling, and 3) investigate extracellular roles of the ciliary pocket in signaling. In summary, I propose to establish a high-resolution map of the architecture and spatial and temporal dynamics of the mammalian ciliary pocket and define its role in supporting ciliary signal transduction. Defects in ciliary structure lead to aberrant signaling in a variety of disease states. The proposed research will expand our understanding of how the architecture of the periciliary membrane supports proper function of the primary cilium and has the potential to contribute new insights into the molecular basis of human diseases such as ciliopathies and cancer.

项目概要纤毛是普遍存在且重要的基于微管的细胞器，参与感觉、发育信号传导、流体流动和细胞运动，其失调会导致一系列人类疾病状态，包括癌症和纤毛病。不动的初级纤毛起到信号天线的作用。它具有独特且严格调节蛋白质和脂质组成，同时保持与质膜连续细胞。适当的纤毛功能取决于纤毛活动的空间分离和高浓度的信号成分。虽然蛋白质已经有了广泛的表征以及构成纤毛、纤毛膜及其基部扩散屏障的脂质，人们知之甚少关于支持正确信号传导的靠近纤毛的膜区域的组成和功能。在许多细胞类型中，成熟的初级纤毛位于微米深的膜内陷中，称为 “纤毛袋”是一个重要但未被充分表征的内吞活动和信号转导中心。这睫状囊的超微结构高度保守，与睫状体和血浆不同膜。很难将睫状袋明确定义为一个独特的区室并确定其对纤毛信号传导和功能的全面贡献。这部分是由于成像的技术挑战衍射区域有限，并且缺乏专门扰乱口袋结构和成分的工具。在这个建议一将通过一系列相互关联的目标并利用创新技术来解决这一差距包括基于邻近的标记和超分辨率显微镜以及功能信号分析，以： 1) 定义纤毛袋的分子组成，2) 确定纤毛袋的结构建立并维持以支持信号传导，3）研究睫状袋的细胞外作用发信号。总之，我建议建立一个高分辨率的建筑和空间地图哺乳动物纤毛袋的时间动态并定义其在支持纤毛信号转导中的作用。纤毛结构的缺陷导致多种疾病状态下的信号异常。拟议的研究将扩大我们对睫状体周围膜的结构如何支持适当的初级纤毛的功能，有可能为人类的分子基础提供新的见解纤毛病和癌症等疾病。