Functional Categorization of Ciliary Motion in PCD

PI：所罗门，乔治M. 原发性纤毛运动障碍（PCD）是一种运动纤毛的遗传异质性疾病， 由于粘膜纤毛清除功能丧失导致的进行性肺病。虽然对遗传学的新理解 已经有助于临床诊断，纤毛的功能测试需要了解和预测 表型变异和对治疗的反应。我们实验室最近的工作已经确定了 睫状体遗传学和新的睫状体表型使用一微米光学相干断层扫描（µOCT）。我们 已经对已知和新的小鼠PCD模型的纤毛跳动模式进行了表型分析。我们已经扩展了这个 通过使用人类鼻上皮细胞对人类起作用。利用这些技术，我们将 我的总体假设是，PCD突变可以是 功能分析以诊断PCD，在机制水平上理解基因型-表型相关性， 并预测对纤毛激动剂的临床反应。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 在原代人细胞中的粘膜纤毛转运缺陷和2）确定是否药理学调节 纤毛功能的增强可以增加纤毛运动和粘液清除的突变体与运动纤毛表达 具体目标如下： 具体目标1：确定基于µ OCT的原发性肝癌功能分析的诊断准确性 人体呼吸道细胞 具体目标2：确定基因型和功能性纤毛表型之间的关系， PCD。具体目标3：确定CBF的药理学调节是否可以挽救PCD中的MCT 有运动纤毛的表达。 本项目通过以下方法探索原发性纤毛运动障碍病理生物学的新概念： 创新性地使用体外成像（µOCT）测量粘膜纤毛运输和纤毛运动， 精确表型临床PCD和遗传学对人体组织中纤毛功能和MCT的影响。在 这样做，我们将建立一个测试治疗方案，以增加MCT和睫状体功能。的 上述职业发展计划和研究目标同样重要， 这个项目的发展。结合强大的指导委员会，遗传学方面的额外培训 和心肺生理学，研究设计，方法学和统计分析，所罗门博士将拥有所有 工具来实现他的职业目标作为一个独立的物理学家科学家。由此带来的机遇 职业发展奖将导致创造一个医生，科学家与必要的技能， 准确和道德地回答有关PCD表型的潜在疗法的重要科学问题， 成功获得未来的独立资金，并为PCD患者的生活带来重要变化

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