Functional Categorization of Ciliary Motion in PCD

派：所罗门，乔治·M。 原发性纤毛运动障碍(PCD)是一种遗传异质性的运动性纤毛疾病，导致 由于粘液纤毛清除障碍而导致的进行性肺部疾病。虽然对遗传学的新理解 纤毛功能测试对临床诊断有帮助，需要了解和预测纤毛功能 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 纤毛遗传学和一微米光学相干断层扫描(µOCT)的新纤毛表型。我们 已经对已知和新的小鼠PCD模型的纤毛搏动模式进行了表型分析。我们已经延长了这一期限 通过使用人类鼻腔上皮细胞对人类产生影响。使用这些技术，我们将 功能性纤毛病变的特征和量化我的总体假设是PCD突变可以是 进行功能分析以诊断PCD，在机理水平上了解基因-表型的相关性， 并预测对睫状肌激动剂的临床反应。这项提议的目标是1)推进μOCT和其他 功能影像分析对PCD相关基因功能后果的诊断和分类 原代人类细胞粘液纤毛运输的缺陷和2)决定了药物调节 纤毛运动功能异常可增强纤毛运动和粘液清除 通过以下具体目标： 具体目标1：确定基于µOCT的初级脑功能分析的诊断准确性 人体呼吸道细胞。 特定目标2：确定儿童功能性纤毛表型与基因的关系 PCD。具体目标3：确定CBF的药理调节是否能挽救PCD的MCT 有动感的纤毛表情。 这个项目探索了原发纤毛运动障碍的病理生物学的新概念 创新地使用粘液纤毛传输和纤毛运动的体外成像(µOCT)测量来诊断和 准确的表型、临床PCD以及遗传学对人体组织中睫状体功能和MCT的影响。在……里面 为此，我们将建立一项测试治疗方案，以增强MCT和睫毛功能。这个 随附的职业发展计划和上述研究目标在 这个项目的发展。再加上一个强大的指导委员会，额外的遗传学培训 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 实现他作为一名独立内科医生兼科学家的职业目标的工具。由此带来的机遇 职业发展奖将产生一名具有以下必要技能的内科科学家 准确和伦理地回答有关PCD表型潜在治疗的重要科学问题， 成功获得未来的独立资助，并在PCD患者的生活中做出重要改变

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