Structure and Function of the Ciliary Pore Complex

睫状孔复合体的结构和功能

基本信息

批准号：
8977649
负责人：
Kristen J. Verhey
金额：
$ 50.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977649
关键词：
Abbreviations Adult Automobile Driving Binding Biological Carrier Proteins Cell physiology Cell surface Cells Cilia Cilium Microtubule Complement Complex Cystic Kidney Diseases Data Defect Development Dimensions Disease Electron Microscopy Erinaceidae Event Flagella Fluorescence Recovery After Photobleaching Growth Factor Image Importins Joubert syndrome Kinesin Lateral Lead Left Life Ligands Link Lipids Lung Membrane Membrane Proteins Methods Microscopy Microtubules Modeling Molecular Monomeric GTP-Binding Proteins Motor Movement Nature Nephronophthisis Nuclear Nuclear Pore Nuclear Pore Complex Nuclear Pore Complex Proteins Organ Organelles Phenotype Physiology Plant Roots Play Precipitation Process Proteins Publishing Resolution Retinitis Pigmentosa Role Running Sensory Signal Transduction Structure Syndrome Techniques Testing Therapeutic Work base body system cell motility ciliopathy human SMO protein human disease novel particle protein protein interaction protein transport public health relevance single molecule spatial relationship spatiotemporal tool trafficking yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Cilia are microtubule-based organelles that are involved in multiple cellular processes including signaling and motility. Protein entry into cilia s a tightly regulated process and defects in cilia-localized proteins are felt to be a root cause of many ciliopathies that manifest as cystic kidney disease, retinitis pigmentosa and/or other defects. The entry of proteins into cilia appears to be controlled at the cilia base where a ciliar pore is hypothesized to exist. Our group has proposed that the ciliary pore is highly analogous to the nuclear pore in its molecular composition and regulatory mechanism. In particular, we have demonstrated that proteins known to be involved in nuclear trafficking - the small GTPase Ran, its binding partners the importins, and nucleoporins - are present at the base or within cilia and regulate protein entry into the ciliary compartment. Based on our Preliminary Data, we now propose a model where two distinct mechanisms regulate entry into the ciliary compartment: entry of cytosolic proteins is regulated by nucleoporins of the ciliary pore complex (CPC) and requires kinesin motors and intraflagellar transport (IFT) whereas entry of membrane proteins is regulated by molecules of the transition zone (TZ) and is IFT-independent. We will test this model using inducible inhibition of nucleoporin and kinesin motor function combined with live-cell, single-molecule, and super-resolution microscopy techniques. These studies will lead the field forward in understanding ciliary gating mechanisms and will make important inroads in defining the nature of the cilia pore and its relation to the nuclear pore.

描述（由申请人提供）：纤毛是基于微管的细胞器，参与多种细胞过程，包括信号传导和运动。蛋白质进入纤毛是一个严格调控的过程，纤毛定位蛋白的缺陷被认为是许多纤毛病的根本原因。表现为囊性肾病、色素性视网膜炎和/或其他缺陷。蛋白质进入纤毛似乎是在纤毛基部被控制的，纤毛基部的纤毛孔被夺走。我们的小组提出，纤毛孔在其分子组成和调节机制方面与核孔高度相似，特别是，我们已经证明了已知参与核运输的蛋白质 - 小 GTPase Ran，其结合伙伴。输入蛋白和核孔蛋白 - 存在于纤毛的基部或内部根据我们的初步数据，我们现在提出了一个模型，其中有两种不同的机制调节进入纤毛室：胞浆蛋白的进入受纤毛孔复合物（CPC）的核孔蛋白调节，并且需要驱动蛋白。马达和鞭毛内运输 (IFT)，而膜蛋白的进入受过渡区 (TZ) 分子调节，并且与 IFT 无关，我们将使用该模型进行测试。核孔蛋白和驱动蛋白运动功能的诱导性抑制与活细胞、单分子和超分辨率显微镜技术相结合，这些研究将引领该领域了解纤毛门控机制，并将在定义纤毛孔的性质方面取得重要进展。及其与核孔的关系。