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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。