Functional Categorization of Ciliary Motion in PCD

PCD 中睫状运动的功能分类

基本信息

批准号：
10322984
负责人：
George Martin Solomon
金额：
$ 15.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2019-01-07 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322984
关键词：
Address Adopted Affect Agonist Anatomy Bronchiectasis Cardiopulmonary Physiology Categories Cell Culture Techniques Cells Cilia Clinical Complement DNA Sequence Alteration Data Defect Development Development Plans Diagnosis Disease Education Epithelial Epithelial Cells Ethics Frequencies Functional Imaging Funding Funding Mechanisms Future Genes Genetic Genotype Goals Host Defense Human Image Image Analysis Imaging Techniques Imaging technology In Situ In Vitro Infection K-Series Research Career Programs Laboratories Link Lung diseases Measures Mentors Methodology Microscopy Modeling Molecular Motion Mucociliary Clearance Mus Mutation Nasal Epithelium Optical Coherence Tomography Outcome Patient Monitoring Patients Pattern Pharmacology Phenotype Physicians Physiology Primary Ciliary Dyskinesias Proteins Protocols documentation Research Research Design Residual state Resolution Respiratory Failure Respiratory System Scientist Severities Sinus Statistical Data Interpretation Surface Techniques Technology Testing Therapeutic Time Tissues Trachea Training Variant Work airway epithelium airway obstruction base career career development cell motility cell type ciliopathy cilium motility clinical diagnostics clinical phenotype clinical predictors clinically significant diagnostic accuracy diagnostic strategy diagnostic tool experience genetic analysis human tissue improved in vivo innovation motility disorder mucus clearance mutant novel novel therapeutic intervention personalized approach predict clinical outcome predicting response preservation response risk stratification skills success tissue culture tool treatment response

项目摘要

PI: Solomon, George M. Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia that results in progressive lung disease due to abrogated mucociliary clearance. While new understandings of the genetics have been helpful for clinical diagnostics, functional testing of cilia are needed to understand and predict phenotypic variation and response to therapy. Recent work in our laboratory has identified a link between ciliary genetics and novel ciliary phenotypes using one-micron optical coherence tomography (µOCT). We have phenotyped the ciliary beating pattern of known and novel murine PCD models. We have extended this work to humans through the use of human nasal epithelial cells. Using these technologies, we will characterize and quantify functional ciliopathies My overall hypothesis is that PCD mutations can be functionally analyzed to diagnose PCD, understand genotype-phenotype correlation on a mechanistic level, and predict clinical response to ciliary agonists. The goals of this proposal are 1) to advance μOCT and other functional imaging analysis to diagnose and categorize the functional consequences of PCD-associated gene defects on Mucociliary transport in primary human cells and 2) determine whether pharmacological modulation of ciliary function can augment ciliary motility and mucus clearance in mutants with motile cilia expression through the following specific aims: Specific Aim 1: Determine the diagnostic accuracy of µOCT-based functional analysis of primary human airway cells. Specific Aim 2: Determine the relationship between genotype and functional ciliary phenotype in PCD. Specific Aim 3: Determine whether pharmacologic modulation of CBF can rescue MCT in PCD with motile cilia expression. This project explores new concepts in the pathobiology of primary ciliary dyskinesia through the innovative use of in vitro imaging (µOCT) measures of mucociliary transport and ciliary motion to diagnose and precisely phenotype clinical PCD and the effect of genetics on ciliary function and MCT in human tissues. In so doing, we will establish a protocol for testing of treatments to augment MCT and ciliary function. The accompanying career development plan and the research aims as outlined above are of equal importance in the development of this project. Combined with a strong mentoring committee, additional training in genetics and cardiopulmonary physiology, study design, methodology, and statistical analysis, Dr. Solomon will have all the tools to achieve his career goal as an independent physician-scientist. The opportunities created by this career development award will result in the creation of a physician-scientist with the skills necessary to accurately and ethically answer important scientific questions about potential therapies for PCD phenotypes, successfully obtain future independent funding, and make important differences in the lives of PCD patients

PI：所罗门，乔治·M。原发性睫状运动障碍（PCD）是一种遗传上异质性纤毛疾病，导致由于废除的粘膜贡清除而导致的进行性肺部疾病。而对遗传学的新理解有助于临床诊断，需要纤毛的功能测试来理解和预测表型变异和对治疗的反应。我们实验室的最新工作已经确定了使用一微米光学相干断层扫描（µOCT）的睫状遗传学和新型睫状表型。我们已经表现出已知和新型鼠PCD模型的睫毛跳动模式。我们已经扩展了这个通过使用人类鼻上皮细胞来对人类作用。使用这些技术，我们将表征和量化功能性纤毛病，我的总体假设是PCD突变可以是在功能上分析以诊断PCD，了解机械水平上的基因型 - 表型相关性，并预测对睫状激动剂的临床反应。该提案的目标是1）推进μoct和其他功能成像分析以诊断和分类PCD相关基因的功能后果原代人细胞中的粘纤毛转运缺陷，2）确定药理调节是否是否睫状功能可以增强纤毛运动的睫状运动和Mutus的清除率在具有纤毛表达的突变体中通过以下特定目的：特定目标1：确定基于µCT的功能分析的诊断精度人气道细胞。特定目标2：确定基因型与功能性睫状表型之间的关系 PCD。特定目标3：确定CBF的药理调制是否可以在PCD中挽救MCT 具有纤毛表达。该项目通过通过体外成像（µOCT）的创新使用粘膜运输和纤毛运动的衡量标准精确表型临床PCD以及遗传学对人体组织中睫状功能和MCT的影响。在因此，我们将建立一项协议，用于测试以增强MCT和睫状功能的治疗方法。参与职业发展计划，该研究的目的如上所述该项目的发展。结合一个强大的心理委员会，对遗传学的额外培训以及心肺生理学，研究设计，方法论和统计分析，所罗门博士将拥有所有作为独立身体科学家实现职业目标的工具。这个创造的机会职业发展奖将导致创建一个身体科学家，并具有必要的技能准确和道德上回答有关PCD表型潜在疗法的重要科学问题，成功获得未来的独立资金，并在PCD患者的生活中产生重要差异