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Regulation of Motile Cilia Assembly in Lung Disease

肺部疾病中活动纤毛组装的调节

基本信息

批准号：
10608147
负责人：
Steven Brody
金额：
$ 78.59万
依托单位：
WASHINGTON UNIVERSITY
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：
2015-08-17 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608147
关键词：
Actins Adaptor Signaling Protein Address Binding Biochemical Biophysics Carrier Proteins Cells Chlamydomonas Chronic Chronic lung disease Cilia Cities Complex Cryoelectron Microscopy Cystic Fibrosis Cytoplasm Cytoplasmic Protein Cytoskeleton Data Development Disease Dynein ATPase Elements Functional disorder Funding Genes Genetic Genetic Diseases Genotype Goals Host Defense Human Link Lung diseases Lung infections Mechanics Microtubules Modeling Motor Movement Mucous body substance Mus Mutation Obstructive Lung Diseases Organism Particulate Pathway interactions Patients Phenotype Positioning Attribute Production Proteins Proteomics Regulation Reporter Reporting Role Route Secure Series Set protein Site Specificity Structure Syndrome Therapeutic Tissues Translating Transportation Tubulin Universities Washington arm biophysical properties cell motility cilium biogenesis cilium motility comparative genetic regulatory protein human tissue injured airway kinetosome multidisciplinary mutant novel particle pathogen protein complex protein function scaffold targeted treatment trafficking

项目摘要

Project Summary/Abstract Cilia dysfunction leads to chronic lung disease, as occurs in the genetic syndrome primary ciliary dyskinesis (PCD) and may contribute to impaired airway clearance in obstructive pulmonary disease (COPD). Unlike cystic fibrosis, which also causes chronic airway destruction, there is no specific therapy for cilia-related diseases. We now know that most PCD mutations result in defective production, transport, or proper placement of ciliary motors along the ciliary axoneme. However, the exact mechanism by which this occurs is not understood, impeding the development of cilia-specific therapeutic strategies. Thus, our goal is to determine how ciliary motor components are directed from the cytoplasm, into the cilia, then find their way to specific sites along the ciliary axoneme. In this proposal, we trace the passage of the multifunctional, heterodimer CCDC39/CCDC40, which when mutant result in disorganized axonemal microtubule structure and severe PCD disease. CCDC39 trafficking serves to identify the mechanisms by which ciliary components move from the cytoplasm, en route to the basal body, and into cilia by intraflagellar transport (IFT). Our preliminary data indicate that: (1) Ciliary cargoes, including CCDC39, bind centriolar satellite proteins that function as “cars” to facilitate trafficking to the basal body; (2) CCDC39/CCDC40 are linked to microtubules in association with two novel “staple” proteins; and (3) CCDC39 is an IFT co-adaptor protein, with ciliary protein MLF1, for cargo delivery to cilia. We hypothesize that movement of ciliary cargo from the cytoplasm to cilia engages transport mechanisms using satellite proteins, then co-adapter proteins, including CCDC39/CCDC40, to properly assemble cilia. We will characterize this series of pathways in the Specific Aims: (1) Determine how components of motile cilia are trafficked from the cytoplasm to basal bodies; (2) Characterize the multifunctional protein CCDC39 by biophysical and biochemical means that will identify the role of novel staple proteins; and (3) Identify the role for CCDC39 and MLF1 as IFT co-adapter proteins in PCD mutants and COPD tissues. The project uses highly integrated strategies that employ models from single cell organisms to human tissues carried out by the multidisciplinary Washington University Cilia Group, to define new pathways for cilia assembly that can be translated to therapies.

项目概要/摘要纤毛功能障碍会导致慢性肺部疾病，如遗传综合征原发性纤毛运动障碍中所发生的那样 (PCD)，并可能导致阻塞性肺疾病 (COPD) 气道清除受损。不像囊性纤维化，也会导致慢性气道破坏，目前没有针对纤毛相关的具体治疗方法疾病。我们现在知道，大多数 PCD 突变会导致生产、运输或适当的缺陷沿着纤毛轴丝放置纤毛马达。然而，发生这种情况的确切机制是不被理解，阻碍了纤毛特异性治疗策略的发展。因此，我们的目标是确定纤毛运动成分如何从细胞质引导到纤毛，然后找到它们的途径沿着睫状轴丝的特定位点。在这个提案中，我们追溯了多功能的历程，异二聚体 CCDC39/CCDC40，突变时会导致轴丝微管结构紊乱，严重的 PCD 疾病。 CCDC39 贩运有助于确定睫状成分移动的机制从细胞质到基体，并通过鞭毛内运输（IFT）进入纤毛。我们的初步数据表明：(1) 纤毛货物，包括 CCDC39，结合中心粒卫星蛋白，其功能为 “汽车”，以方便贩运到基础机构； (2) CCDC39/CCDC40与微管关联具有两种新颖的“主食”蛋白质； (3) CCDC39 是一种 IFT 协同接头蛋白，具有纤毛蛋白 MLF1，用于货物运送到cilia。我们假设纤毛货物从细胞质到纤毛的运动涉及使用卫星蛋白的转运机制，然后使用辅助接头蛋白（包括 CCDC39/CCDC40）正确组装纤毛。我们将在具体目标中描述这一系列路径：（1）确定如何运动纤毛的成分从细胞质运输到基体； (2) 表征通过生物物理和生化手段鉴定多功能蛋白CCDC39将鉴定新型主食的作用蛋白质； (3) 确定 CCDC39 和 MLF1 作为 IFT 辅助接头蛋白在 PCD 突变体中的作用，慢性阻塞性肺病组织。该项目采用高度集成的策略，利用单细胞生物模型由华盛顿大学多学科纤毛小组开展的人体组织研究，以确定新的途径用于可转化为治疗的纤毛组装。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Centrosome-dependent microtubule modifications set the conditions for axon formation.

DOI：
10.1016/j.celrep.2022.110686
发表时间：
2022-04-19
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Meka, Durga Praveen;Kobler, Oliver;Hong, Shuai;Friedrich, Carina Meta;Wuesthoff, Souhaila;Henis, Melad;Schwanke, Birgit;Krisp, Christoph;Schmuelling, Nessa;Rueter, Rene;Ruecker, Tabitha;Betleja, Ewelina;Cheng, Tao;Mahjoub, Moe R.;Soba, Peter;Schluter, Hartmut;Fornasiero, Eugenio F.;de Anda, Froylan Calderon
通讯作者：
de Anda, Froylan Calderon

Super-Resolution Microscopy and FIB-SEM Imaging Reveal Parental Centriole-Derived, Hybrid Cilium in Mammalian Multiciliated Cells.

DOI：
10.1016/j.devcel.2020.09.016
发表时间：
2020-10-26
期刊：
Developmental cell
影响因子：
11.8
作者：
Liu Z;Nguyen QPH;Nanjundappa R;Delgehyr N;Megherbi A;Doherty R;Thompson J;Jackson C;Albulescu A;Heng YM;Lucas JS;Dell SD;Meunier A;Czymmek K;Mahjoub MR;Mennella V
通讯作者：
Mennella V

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.

DOI：
10.1038/s41419-023-05720-4
发表时间：
2023-03-17
期刊：
CELL DEATH & DISEASE
影响因子：
9
作者：
Lewis, Michael;Terre, Berta;Knobel, Philip A.;Cheng, Tao;Lu, Hao;Attolini, Camille Stephan-Otto;Smak, Jordann;Coyaud, Etienne;Garcia-Cao, Isabel;Sharma, Shalu;Vineethakumari, Chithran;Querol, Jessica;Gil-Gomez, Gabriel;Piergiovanni, Gabriele;Costanzo, Vincenzo;Peiro, Sandra;Raught, Brian;Zhao, Haotian;Salvatella, Xavier;Roy, Sudipto;Mahjoub, Moe R.;Stracker, Travis H.
通讯作者：
Stracker, Travis H.

Magnify is a universal molecular anchoring strategy for expansion microscopy.

DOI：
10.1038/s41587-022-01546-1
发表时间：
2023-06
期刊：
NATURE BIOTECHNOLOGY
影响因子：
46.9
作者：
Klimas, Aleksandra;Gallagher, Brendan R.;Wijesekara, Piyumi;Fekir, Sinda;DiBernardo, Emma F.;Cheng, Zhangyu;Stolz, Donna B.;Cambi, Franca;Watkins, Simon C.;Brody, Steven L.;Horani, Amjad;Barth, Alison L.;Moore, Christopher I.;Ren, Xi;Zhao, Yongxin
通讯作者：
Zhao, Yongxin

Variations in infection control practices suggest a need for guidelines in primary ciliary dyskinesia patient care.

感染控制实践的变化表明需要制定原发性纤毛运动障碍患者护理指南。