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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.

项目总结/文摘

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

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.

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

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。