REGULATION OF MOTILE CILIA ASSEMBLY IN LUNG DISEASE

肺部疾病中活动纤毛组件的调节

• 批准号: 8941243
• 负责人: Steven Brody
• 金额: $ 57.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8941243
• 关键词: Address; Algae; Apical; Asthma; Bronchiectasis; Carrier Proteins; Cells; Characteristics; Chlamydomonas; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Cilia; Collection; Complex; Congenital Heart Defects; Cytoplasm; Cytoplasmic Protein; Data; Defect; Development; Disease; Docking; Dynein ATPase; Epithelial Cells; Event; Failure; Functional disorder; Future; Gene Proteins; Genes; Genetic; Genetic Predisposition to Disease; Goals; Hereditary Disease; Host Defense; Human; In Vitro; Infection; Inherited; Knowledge; Lead; Length; Link; Lung; Lung diseases; Microtubules; Modeling; Molecular; Motor; Mutate; Mutation; Nuclear; Outcome; Particulate; Pathway interactions; Phosphotransferases; Primary Ciliary Dyskinesias; Proteins; Regulation; Regulatory Pathway; Reporting; Role; Staging; Structure; Suppressor Genes; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Zebrafish; arm; cell motility; cilium biogenesis; forward genetics; functional restoration; gain of function; genetic manipulation; improved; in vivo; kinetosome; loss of function mutation; member; mutant; novel; pathogen; programs; protein complex; protein transport; public health relevance; targeted treatment; therapy development; trafficking

 DESCRIPTION (provided by applicant): Failure of airway clearance is a characteristic feature of chronic airway disorders. Evidence that an intact mucociliary apparatus is essential for clearance derives from studies of genetic disease of cilia as well as reports that cilia dysfunctio may contribute to chronic obstructive pulmonary disease (COPD) and asthma. Comprehensive collections of ciliary genes and proteins have contributed to the rapid pace of progress in the identification of genetic etiologies of the syndrome of motile cilia dysfunction, called primary ciliary dyskinesia (PCD). However, there are no specific therapies for this disease that ultimately progresses to bronchiectasis. Here, we address a key set of questions to gain a more complete understanding of the assembly and regulation of motile cilia. Using novel genes mutated in PCD as a guide, we have uncovered specific regulatory steps that are critical for the assembly of motile cilia and offer the prospect of therapeutic intervention to augment ciliogenesis. Our preliminary data define a pathway for motile ciliogenesis that (i) commences at the earliest point of motor protein preassembly in the cytoplasm controlled by HEATR2, (ii) is functionally linked to a network that traffics protein from the cytoplasm to the basal bodies and motile cilia regulated by CCDC11, and (iii) requires the proteins CCDC39 and CCDC40 to establish the proper organization of motors and microtubules within the motile cilium. We show that mutation or depletion of each of these molecular linchpins results in unsuccessful motile cilia biogenesis and function as expected. We also uncover tractable mechanisms at each point of the pathway that we show are modified by the genetic disruption of novel suppressor genes to remediate cilia defects. Our preliminary and proposed studies take advantage of complementary models of primary multiciliated human airway epithelial cells, genetically deficient strains of zebrafish and the alga Chlamydomonas, which together provide in vitro and in vivo analysis and rapid genetic manipulation of cilia assembly pathways. Using these strategies, we will probe the assembly, trafficking and activity of dynein motor assembly in the following aims: (1) Identify the preassembly pathways required for dynein motor protein complex delivery; (2) Identify the regulation of motor protein trafficking from basal bodies to cilia; (3) Identify genes that can restore function to cells lacking docking and assembly factors for the motor proteins. We propose that manipulation of these pathways will offer possibilities of devising molecular therapies for defects in motile cilia.