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Cellular and Molecular Features of Gene Mutations in Primary Ciliary Dyskinesia

原发性纤毛运动障碍基因突变的细胞和分子特征

基本信息

批准号：
10378548
负责人：
Steven Brody
金额：
$ 56.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378548
关键词：
Address Animal Model Appearance Autophagocytosis Behavior Biochemical Biological Assay Bronchiectasis Cells Characteristics Chronic Chronic Sinusitis Chronic lung disease Cilia Code Complex Consequentialism Cystic Fibrosis Cytoplasm Data Defect Disease Dynein ATPase Failure Fluorescence Resonance Energy Transfer Gene Mutation Genes Genetic Genetic Diseases Genetic study Goals Heart Abnormalities Heat shock factor Human Image Impairment Infertility Inherited Interruption Lead Lung diseases Mass Spectrum Analysis Missense Mutation Modeling Molecular Molecular Chaperones Motor Mutate Mutation Nature Neurodegenerative Disorders Pathologic Pathway interactions Phase Primary Ciliary Dyskinesias Process Proteins Regulatory Pathway Structural Protein Structure Syndrome Therapeutic Transmission Electron Microscopy candidate marker cell motility chronic respiratory disease cilium biogenesis cilium motility gene discovery member motility disorder motor impairment multicatalytic endopeptidase complex mutant protein aggregation protein degradation protein function protein protein interaction proteostasis recurrent infection scaffold skeletal trafficking

项目摘要

Summary The genetic syndrome primary ciliary dyskinesia (PCD) is characterized by defects in cilia motility resulting in bronchiectasis, chronic sinusitis, infertility and cardiac malformations. Intense efforts over the past decade have uncovered pathways required for cilia assembly and discovered genes that are mutant in PCD. The next goal is to understand the specific cellular consequences of different classes of mutations to identify therapeutic avenues, similar to the approach used for cystic fibrosis. Cilia motility is dependent on dynein motors, which are fixed in large complexes on the skeletal axoneme of cilia. Genes that code for these dynein motors commonly harbor PCD mutations. However, studies in model organisms and human cells have revealed that dyneins must be prepared in the cytoplasm by dynein axoneme assembly proteins (DyAPs). We found that DyAPs colocalize with dyneins in cytoplasmic foci of multiciliated cells. Mutation in DyAPs results in an absence of dynein motors within the cilia and consequentially, impaired cilia function, also resulting in PCD. We have recently identified a subset of DyAPs composed of HEATR2/SPAG1/DNAAF2, which form an early scaffold to function in an initiation phase of dynein assembly. We propose that this scaffold engages with a second group of DyAPs, that we term the folding phase complex, which carries out dynein assembly for transport to the cilia. We observed that mutations in the initiation phase DyAPs result in the formation of cytoplasmic aggregates tagged with the proteostasis adapter SQSTM1/p62, suggesting that abnormal protein processing leads to pathway interruption. Consistent with this concept, these aggregates contain all three proteins of the initiation phase complex. We hypothesize that mutations in DyAPs interrupt the complex function, lead to the formation of intracellular aggregates of non- functioning machinery and a failure to move dynein motors to the cilia. We address this question with these aims: (1) A functional analysis of human mutations of the initiation phase DyAPs to determine their effect on the pathway related to the formation of aggregates, intracellular trafficking, and protein interactions with other DyAPs and (2) a biochemical analysis to identify the composition of the aggregates and the associated activity of the cellular proteostasis pathways to mitigate formation. Our goal is to identify factors related to the formation of DyAP aggregates, determine how the DyAP pathway is interrupted and ask if aggregates formation can be manipulated to rescue sufficient amounts of protein for function, as a first step toward conceptualizing a specific treatment for one class of PCD mutations.

总结