An important component of lung defense is the efficiency of mucociliary clearance (MCC). Primary ciliary dyskinesia (PCD) is a human genetic model of abnormal ciliary function and defective MCC. The overall goals of this project are to relate the molecular etiology of PCD to the ciliary phenotype (ultra structure; ciliary beat frequency and pattern). We hypothesize that certain abnormalities in ciliary ultra structure (particularly defective outer and inner dynein arms) reflect genetic mutations, and that discrete groups of genes encode each of those structures. Moreover, we hypothesize that mutations in genes encoding for outer dynein arm versus inner dynein arm proteins will be associated with different effects on ciliary beat frequency and waveform. Finally, we hypothesize that we will discover disease-causing mutations in PCD by a candidate gene approach, focused on genes encoding proteins in the dynein arms and central complex. To test our hypotheses, we have accumulated a cohort (n=86) of PCD patients who fulfill rigorous diagnostic criteria. In these (and an additional 60) PCD patients, we will determine ciliary ultra structure by transmission electron microscopy (TEM) and functional phenotype of PCD cilia using high-speed video-microscopy techniques. The strategy to test for disease-causing genetic mutations in PCD will use several different approaches, including an approach to narrow the search for candidate genes by using intra-genic polymorphisms, to test for """"""""linkage"""""""" (exclusion mapping) within individual families. Taken together, these studies will allow us to determine correlations between ciliary ultra structure/function and genotype. Ultimately, we will develop a better understanding of the pathogenesis of airway disease resulting from abnormal ciliary function and defective mucociliary clearance. From a broader perspective, the identification of the genetic basis of PCD in patients with known ultrastructural defects will later provide the opportunity to test for """"""""milder"""""""" genetic forms of ciliary dysfunction that predispose to more common airways diseases.
| Rosenfeld, Margaret; Ostrowski, Lawrence E; Zariwala, Maimoona A (2018) Primary ciliary dyskinesia: keep it on your radar. Thorax 73:101-102 |
| Bustamante-Marin, Ximena M; Ostrowski, Lawrence E (2017) Cilia and Mucociliary Clearance. Cold Spring Harb Perspect Biol 9: |
| Blackburn, Kevin; Bustamante-Marin, Ximena; Yin, Weining et al. (2017) Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance. J Proteome Res 16:1579-1592 |
| Leigh, Margaret W; Ferkol, Thomas W; Davis, Stephanie D et al. (2016) Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents. Ann Am Thorac Soc 13:1305-13 |
| Shapiro, Adam J; Zariwala, Maimoona A; Ferkol, Thomas et al. (2016) Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol 51:115-32 |
| Knowles, Michael R; Zariwala, Maimoona; Leigh, Margaret (2016) Primary Ciliary Dyskinesia. Clin Chest Med 37:449-61 |
| Lobo, Jason; Zariwala, Maimoona A; Noone, Peadar G (2015) Primary ciliary dyskinesia. Semin Respir Crit Care Med 36:169-79 |
| Lucas, Jane S; Behan, Laura; Dunn Galvin, Audrey et al. (2015) A quality-of-life measure for adults with primary ciliary dyskinesia: QOL-PCD. Eur Respir J 46:375-83 |
| Fedick, Anastasia M; Jalas, Chaim; Treff, Nathan R et al. (2015) Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. Mol Genet Genomic Med 3:137-42 |
| Davis, Stephanie D; Ferkol, Thomas W; Rosenfeld, Margaret et al. (2015) Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med 191:316-24 |
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